Decoding m6
A mRNA methylation by reader proteins in cancer
Bing Han a
, Saisai Wei a
, Fengying Li a
, Jun Zhang a
, Zhongxiang Li b
, Xiangwei Gao a,*
a Sir Run-Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China b Medical Research Institute, Baoan Women’s and Children’s Hospital, Jinan University, Shenzhen, 518133, China
A modification
YTH domain protein
mRNA metabolism
A editor
-methyladenosine (m6
A), the most prevalent internal modification in eukaryotic mRNAs, regulates gene
expression at the post-transcriptional level. The reader proteins of m6
A, mainly YTH domain-containing proteins,
specifically recognize m6
A-modified mRNAs and regulate their metabolism. Recent studies have highlighted
essential roles of m6
A readers in the initiation and development of human cancers. In this review, we summarize
recent findings about the biological functions of YTH domain proteins in cancers, the underlying mechanisms,
and clinical implications. Gene expression reprogramming by dysregulated m6
A reader proteins offers potential
targets for cancer treatment, while targeted m6
A editors and readers provide tools to manipulate m6
A meta￾bolism in cancers.
1. Introduction
Chemical modifications of RNA are critical for gene expression at the
post-transcriptional level, which subsequently induce changes in bio￾logical outputs. In particular, the N6
-methyladenosine (m6
A) modifica￾tion on RNAs, methylation at the sixth position nitrogen atom of
adenosine (A), is an essential regulator because of its high abundance: it
has been found in 0.1–0.4 % of messenger RNA (mRNA) adenosine
residues in diverse eukaryotic cells [1–3]. Despite the early discovery in
various cellular mRNAs in the 1970s, the distribution of m6
A was
recently clarified with the development of detecting methodologies
A-seq and its derivatives) [4,5]. These methods allow analyzing m6
distribution at the transcriptomic level, opening up the era of “epi￾transcriptomics”. Mapping of m6
A in different organisms revealed a
highly conserved feature of this modification. A consensus motif of m6
modification, RRACH ([G/A/U][G/A]m6
AC[U/A/C]), has been identi￾fied by the m6
A-seq data [5,6]. As for the exact positions, m6
enriched around stop codons and in the 3′ untranslated regions (3′
UTRs) [4,5]. In addition to methodological breakthrough, the charac￾terization of its enzyme system further brought this modification into
the spotlight [7]. It is now known that the m6
A modification is
dynamically regulated by methyltransferases (‘writers’) and demethy￾lases (‘erasers’) [8,9]. The writers, including core methyltransferase
components (METTL3 and METTL14) and their cofactors (WTAP,
RBM15, HAKAI, VIRMA, and ZC3H13), promote the deposition of m6
on mRNAs [10]. The reversibility of m6
A relies on erasers, including
FTO and ALKBH5, leading to the removal of m6
A modifications for a
balanced equilibrium [7,9].
2. “Reader” proteins regulate the fate of m6A-modified mRNAs
A methylation alters Watson-Crick base pairing strength, RNA
secondary structure, or protein-RNA interactions, which in turn affects
gene expression by modulating almost all aspects of RNA metabolism,
including processing, localization, translation, and decay [11–13].
“reader” proteins directly regulate RNA fate. Combined approaches
involving RNA affinity chromatography and mass spectrometry have
been used to identify several m6
A readers, including YT521-B homology
domain-containing proteins (YTHDF1-3 and YTHDC1-2) [5],
insulin-like growth factor 2 (IGF2) mRNA-binding proteins (IGF2BP1-3)
[14], FMR1 [15], and heterogeneous nuclear ribonucleoprotein
(HNRNP) protein family members [16,17]. These reader proteins
decode m6
A and decide the metabolic fate of modified mRNAs, indi￾cating that they are crucial in the regulation of RNA metabolism and
post-transcriptional gene expression.
A readers process RNA at least through 3 mechanisms: selectively
binding, weakening the cognate binding proteins, altering the secondary
structure of RNA and RNA-protein interactions [8]. Highly conserved
YTH domain proteins selectively bind to m6
A modifications with high
affinity and a large binding interface, further altering the secondary
structure [18]. Interestingly, these m6
A readers have distinguishing
* Corresponding author.
E-mail address: [email protected] (X. Gao).
Contents lists available at ScienceDirect
Cancer Letters
journal homepage: www.elsevier.com/locate/canlet
Received 13 May 2021; Received in revised form 25 July 2021; Accepted 28 July 2021
Cancer Letters 518 (2021) 256–265
features of RNA processing. YTHDF1 has recently been extensively
studied as a cytoplasmic m6
A reader. YTHDF1 binds to m6
A at exact G
[G > A](m6
A)C sites and promotes translation initiation by interacting
with initiation factors and ribosomes [19]. As a homologous gene of
YTHDF1, YTHDF2 was identified by RNA immunoprecipitation (RIP)
and photoactivatable ribonucleotide crosslinking and immunoprecipi￾tation (PAR-CLIP) experiments to have a conserved G(m6
A)C[U > A]
motif, and this protein plays an important role in RNA decay by
recruiting the mRNAs to processing bodies (P-bodies) [20]. With similar
sequence identity to YTHDF2, YTHDF3 facilitates m6
mRNA translation and decay together with YTHDF1 and YTHDF2 [21,
22]. YTHDC2, another cytoplasmic YTH family member, regulates
mRNA stability by interacting with the 5′
-3′ exoribonuclease XRN1 and
enhances the translation efficiency of its targets in spermatogenesis and
oogenesis [23,24]. However, IGF2BPs represent a different facet of the
A reading process, mainly promoting mRNA stability and translation
by recognizing the consensus GG(m6
A)C sequence [14]. As for
nuclear-specific m6
A readers, YTHDC1 preferentially recognizes the GG
A)C sequence and mainly functions in mRNA splicing and nuclear
export [25–27]. Heterogeneous nuclear ribonucleoprotein G and C
(HNRNPG/HNRNPC) are other two nuclear readers that bind m6
A to
regulate alternative splicing [16,28,29]. Additionally, another hnRNP
family protein, HNRNPA2B1, binds to m6
A in the pri-miRNA to facilitate
miRNA processing by recruiting a microprocessor [17] (Fig. 1).
3. Manipulating YTH domain protein-regulated m6
A metabolism
Recently developed m6
A editors offer a way to manipulate m6
specifically in individual transcripts [30–32]. Based on CRISPR/Cas
system, these editors compose a methyltransferase or a demethylase
fused with a catalytically inactive Cas proteins (dCas9 or dCas13). With
the help of guide RNAs (gRNAs), site-specific m6
A incorporation or
demethylation in specific transcripts could be achieved (Fig. 2). Studies
using these editors demonstrated that single site methylation in different
mRNA regions may play different roles, either promoting mRNA trans￾lation or degradation. In addition to these m6
A editors, targeted m6
readers have also been developed by fusing m6
A reader proteins,
YTHDF1 or YTHDF2, to dCas13b [33]. The fusion proteins can target the
reader to specific RNA of interest using gRNA (Fig. 2). Tethering tar￾geted mRNA with the fusion proteins can trigger enhanced protein
Fig. 1. The functions of m6
A reader proteins in
mRNA metabolism.
The m6
A reader proteins recognize m6
A and
determine target mRNA fate. The nuclear m6
reader proteins YTHDC1, HNRNPG, and
HNRNPA2B1 regulate mRNA splicing, nuclear
export, and pre-miRNA processing, while the
cytosolic m6
A reader proteins YTHDF1-3,
YTHDC2, and IGF2BP1-3 regulate mRNA trans￾lation and decay.
B. Han et al.
Cancer Letters 518 (2021) 256–265
production or RNA degradation. The development of dCas-based tar￾geted m6
A editors or readers reveal the effect of individual m6
A modi￾fications and dissect their functional roles.
4. The roles of YTH domain proteins in cancer initiation and
Abnormal epigenetic regulation contributes to cancer initiation and
development, during which m6
A has gained increasing attention in
cancer biology [34–36]. m6
A modification affects many cancer pro￾cesses through writers, erasers and readers, such as cancer initiation,
progression, metastasis, therapeutic response and cancer relapse [35].
For m6
A readers, accumulated evidence has shown that YTH domain
proteins have essential roles in various complicated cancer pathogen￾esis. Because of the various RNA fate outcomes mediated by these
readers, the m6
A machinery can play either oncogenic or
tumor-suppressor roles in different cancer contexts. YTHDF1/3 and
YTHDC2 are usually critical in promoting oncogene translation and thus
act as positive tumor markers. However, YTHDF2 is reported to have
dual roles in cancers that depend on the degradation of its target
mRNAs. We briefly summarized the recent studies on the functions of
YTH domain proteins in various cancers (Table 1). The dysregulation of
A readers in human cancers highlights the potential of using these
proteins as new biomarkers and therapeutic targets in clinical practice.
5. Aberrant expression of YTH domain proteins in cancers
Emerging data have suggested that aberrant expression of YTH
proteins in many types of cancers (Table 1) could be strongly associated
with cancer progression and treatment outcomes. Many studies have
shown an increase of YTHDF1 expression in cancers, indicating a posi￾tive correlation with cancer pathogenesis (Table 1). However, how
YTHDF1 expression programs cells to adapt to long-term cancer envi￾ronmental changes remains largely unknown. DNA copy number alter￾ations [38] or transcriptional regulation [37] are both suspected to
account for the overexpression of YTHDF1 in certain cancers. For
example, in colorectal cancer (CRC), the oncogenic transcription factor
c-Myc was shown to be associated with the 5′ region of the transcription
start site of the YTHDF1 gene, indicating that c-Myc promotes YTHDF1
expression in CRC cells. Posttranscriptional regulation is also a key part
of controlling YTHDF1 expression. In the intestine, the activated
Wnt/APC signaling pathway promotes YTHDF1 translation by inter￾acting with its 5′ UTR [39]. MiR-376c was reported to directly target the
UTR of YTHDF1 in non-small-cell lung cancer (NSCLC) cells [40].
Moreover, YTHDF1 could be regulated by USF1 and c-Myc at both the
mRNA and protein levels in hepatocellular carcinoma (HCC) [49].
Despite the fact that YTHDF1 is dysregulated in cancers or at least can be
a risk factor for cancer initiation and prognosis, future research needs to
identify the upstream regulators of YTHDF1.
YTHDF2 has been found to participate in many cancers and might be
associated with cancer progression. Interestingly, YTHDF2 expression is
markedly inconsistent: it is upregulated in some types of cancers and
downregulated in others. For example, YTHDF2 is highly expressed in
bladder cancer, glioblastoma, acute myeloid leukemia (AML), lung
cancer, ovarian cancer and prostate cancer but expressed at low levels in
gastric cancer. Furthermore, YTHDF2 can act as either an oncogene or a
tumor suppresser in HCC. Similar to the situation for other m6
A readers,
evidence of how YTHDF2 responds to the cancer microenvironment is
still limited. Hypoxia has been identified as a key driver of low YTHDF2
expression in HCC, and induction of HIFs, such as HIF-1α and HIF-2α,
has been proven to mediate and enhance YTHDF2 function [78,79].
Recently, miRNAs have also been revealed as regulators of YTHDF2
expression. Luciferase reporter assays and statistical analysis confirmed
that YTHDF2 is a direct target gene of miR-145 in ovarian cancer [86]
and miR-495/miR-493-3p in prostate cancer [88,89].
6. YTH proteins in colorectal cancer
Colorectal cancer (CRC) is the third leading cause of cancer-related
death in both men and women worldwide. However, many cancer
cases and deaths could be prevented with appropriate screening and
surveillance, which indicates the high clinical need for precise tumor
biomarkers and therapeutic targets. m6
A related genes are found
abundantly expressed in colon cancer, including reader protein YTHDC1
and HNRNPC [94]. Recently, most related studies have indicated
YTHDF1 as a potential oncogene in CRC. Given that aberrant
Wnt/β-catenin signaling is the driving force for intestinal tumorigenesis,
some studies have focused on how YTHDF1 interacts with this pathway.
The studies revealed that YTHDF1 is upregulated in CRC tissues versus
normal tissues [39–41]. Deletion of the YTHDF1 gene in mouse intes￾tinal stem cells (ISCs) induces tumor shrinkage and prolongs survival by
blocking the Wnt signaling pathway [39]. In addition to playing a role in
ISCs, YTHDF1 is also involved in promoting cancer stem-cell like activity
by enhancing Wnt activity, which further regulates tumorigenicity in
human CRC [40]. According to The Cancer Genome Atlas (TCGA)
database, the expression of YTHDF1 in CRC also shows a positive cor￾relation with an important Wnt target gene, c-Myc. Mechanistically,
c-Myc activates the transcriptional activity of YTHDF1, promoting
cancer cell proliferation and increasing chemosensitivity [41]. However,
univariate and multivariate Cox regression analyses have clarified that
YTHDF1 is a negative prognostic factor for colon cancer [42]. Studies
revealed lower expression in the high-risk cancer group, indicating good
value for predicting prognosis. Further studies implied that YTHDF1
identifies the m6
A-modified ANKLE1 transcript, a tumor suppressor in
CRC [106], indicating that YTHDF1 may be required for
ANKLE1-regulated CRC inhibition and prevention. Similar to YTHDF1,
YTHDC2 contributes to colon cancer metastasis by promoting HIF-1α
translation, suggesting that YTHDC2 is a potential biomarker for diag￾nosis and treatment response evaluation for colon cancer patients [107].
In CRC, YTHDF3 was identified as a novel target of YAP signaling, by
which YTHDF3 selectively binds to m6
A-modified GAS5 to promote its
decay and triggers CRC proliferation and metastasis [92]. Unlike that of
other YTH domain proteins, the expression of YTHDF2 was unaffected in
CRC tissues compared to nontumor tissues. Nonetheless, the binding of
YTHDF2 to SOX4 mRNA can be increased to induce the degradation of
SOX4, indicating another view of the regulation and impact of m6
A on
CRC [73]. Another study shows that high expression of METTL3 pro￾motes m6
A-modified SOX2 mRNAs, which is subsequently recognized by
IGF2BP2 and leads to inhibition of SOX2 mRNA degradation [105].
Although these observations provide the significant signatures of YTH
domain proteins in CRC progression, more details and the related
mechanisms need to be uncovered.
Fig. 2. Schematic of targeted m6
A editors and readers.
Targeted m6
A editors or readers have been developed by fusing m6
A writers,
erasers, or readers to dCas13b/dCas9. The fusion proteins can target the mRNAs
of interest with the help of gRNA and regulate their metabolism.
B. Han et al.
Cancer Letters 518 (2021) 256–265
Table 1
Functional characterization of YTH domain-containing proteins in cancers.
Cancer Expression Targets and Mechanism Role Reference
YTHDF1 Breast cancer Upregulated Not mentioned. Positive prognostic signature [37]
Upregulated Positive associated with CDK1,
Positive prognostic signature [38]
Colorectal cancer Upregulated Enhances TCF7L2 translation. Oncogene [39]
Upregulated Increases Wnt/β-catenin activity. Oncogene [40]
Upregulated Not mentioned. Oncogene [41]
Downregulated Not mentioned. Negative prognostic signature [42]
Unknown Facilitates ANKLE1 expression. Tumor suppressor [43]
Gastric cancer Unaffected Not mentioned. Tumor suppressive signature [44]
Upregulated Not mentioned. Positive prognostic signature [45]
Upregulated Not mentioned. Oncogene [46]
Upregulated Not mentioned. Oncogene [47]
Upregulated Promotes translation of Snail. Oncogene [48]
Upregulated Promotes FZD5 mRNA translation. Oncogene [49]
Unknown Increases the stability of FOXO3
Oncogene [50]
Lung cancer Upregulated Promotes YAP mRNA translation. Oncogene [51,52]
Upregulated Promotes PRPF6 mRNA expression. Oncogene [53]
Upregulated Targets CDKs and Keap1-Nrf2-
AKR1C1 axis
Dual effect [54]
Upregulated Positive prognostic signature [55]
Upregulated in tumors but downregulated in
higher pathological stages
Not mentioned. Dual effect [56]
Upregulated Disrupts the Wnt/b-catenin pathway. Positive therapeutic target [57]
Melanoma Unknown Promotes HINT2 translation. Oncogene [58]
Upregulated Interactes with CDK1/2. Positive therapeutic target [59]
Ovarian cancer Upregulated Augments EIF3C translation. Oncogene [60]
Unaffected Promotes TRIM29 translation. Oncogene [61]
Cervical cancer Unknown Induces PDK4 expression. Positive therapeutic target [62]
Upregulated Enhances HK2 stability. Positive therapeutic target [63]
Squamous cell
Upregulated Not mentioned. Positive prognostic signature [64]
Upregulated Promotes c-Myc stability. Oncogene [65]
Upregulated Enhances TFRC expression. Positive therapeutic target [66]
Merkel Cell Carcinoma Upregulated Activates eIF3 translation. Oncogene [67]
Abdominal aortic
Upregulated Not mentioned. Unknown [68]
Glioma Upregulated Not mentioned. Positive prognostic signature [69]
Upregulated Not mentioned. Positive prognostic signature [70]
YTHDF2 Bladder cancer Upregulated Promotes SETD7, KLF4 degradation. Oncogene [71]
Cervical cancer Unknown Mediates GAS5 RNA degradation. Potential therapeutic target [72]
Colorectal cancer Unaffected Promotes SOX4 mRNA degradation. Potential therapeutic target [73]
Gastric cancer Downregulated Promotes FOXC2 degradation. Negative prognostic signature [74]
Glioblastoma Upregulated Stabilizes MYC, VEGFA transcripts. Potential therapeutic target [75]
Upregulated Positively correlated with PD-1, TIM-
3 and CTLA-4.
Positive prognostic signature [76]
Upregulated Facilitates LXRA, HIVEP2 mRNA
Potential prognostic signature [77]
Downregulated Proceses IL11, SERPINE2 mRNA
Pptential therapeutic target [78]
Downregulated Destabilizing EGFR mRNA. Tumor suppressor [79]
Unknown Mediates SOCS2 mRNA degradation. Potential therapeutic target [80]
Upregulated Not mentioned. Positive prognostic signature [81]
Upregulated Increases OCT4 translation. Potential therapeutic target [82]
Acute myeloid
Upregulated Destabilizes TNFRSF1B mRNA. Potential therapeutic target [83]
Unknown Reduces PFKP, LDHB expression. Negative prognostic signature [84]
Lung cancer Upregulated Facilitates 6PGD mRNA translation. Potential prognostic signature [85]
Ovarian cancer Upregulated Inversely correlated with miR-145. Positive therapeutic target [86]
Pancreatic cancer Unknown Promotes PER1 mRNA degradation. Potential diagnostic and
Prostate cancer Upregulated Facilitates MOB3B mRNA
Potential therapeutic target [88]
Upregulated Not mentioned. Positive therapeutic target [89]
Upregulated Induces LHPP, NKX3-1 mRNA
Potential diagnostic and
therapeutic target
YTHDF3 Breast cancer Upregulated Positive associated with CDK1,
Positive prognostic signature [38]
Upregulated Induces ST6GALNAC5, GJA1
Potential prognostic signature [91]
Colorectal cancer Upregulated Facilitates GAS5 degradation. Potential prognostic signature [92]
Unknown Enhancing Zeb1 mRNA stability. Potential therapeutic target [93]
YTHDC1 Colorectal cancer Upregulated Not mentioned. Positive therapeutic target [94]
Glioblastoma Unaffected Promotes SRSF decay. Potential therapeutic target [95]
(continued on next page)
B. Han et al.
Cancer Letters 518 (2021) 256–265
7. YTH proteins in liver cancer
Hepatocellular carcinoma (HCC) is the most common type of pri￾mary liver cancer [108]. The high prevalence of HCC has long been
attributed to chronic viral hepatitis, while other risk factors, particularly
genetic or epigenetic susceptibility, are gaining importance. Studies
have shown that HCC is highly associated with abnormal m6
A deposi￾tion [80,109]. Interestingly, m6
A modification in these studies showed
quite different effects on HCC progression: METTL3 promoted HCC via
A modification, but METTL14 was an adverse prognostic factor in
HCC patients. Thus, the final outcome of m6
A modification in HCC could
be determined by assessing m6
A-containing mRNAs and their readers.
Recently, a correlation analysis using the TCGA database showed
that YTHDF1 is significantly overexpressed in HCC and positively
associated with pathology stage, implying that YTHDF1 is a potential
new therapeutic and prognostic marker in HCC [46]. Another similar
study revealed the independent predictive value of both YTHDF1 and
METTL3 for HCC patient overall survival [47]. In addition, in vitro and
in vivo evidence indicated that YTHDF1 induces the progression of
migration, invasion and epithelial-mesenchymal transition (EMT) in
HCC cells by regulating Snail mRNA translation [48]. In addition, Wnt
receptor-FZD5 is another YTHDF1 target at the translational level in
HCC. YTHDF1 promotes HCC cell proliferation and metastasis by
accelerating the translational output of FZD5 mRNA in an m6
A-de￾pendent manner [49]. For HCC therapy, resistance to sorafenib (a
first-line treatment for advanced HCC) remains a problem in developing
individual therapeutic strategies. YTHDF1 was demonstrated to have an
important role in modifying the hypoxic tumor environment by identi￾fying FOXO3 mRNA. This study validated that METTL3 mediates and
that YTHDF1 recognizes FOXO3 methylation, leading to inhibition of the
autophagy signaling pathway to maintain sorafenib sensitivity in HCC
[110]. Therefore, YTHDF1 may act as an oncogene and has the potential
to serve as a positive molecular biomarker for evaluating the prognosis
and treatment response of HCC patients. As a synergy factor of YTHDF1
in protein synthesis, YTHDF3 enhances the stability and lifetime of
A-methylated Zeb1 mRNA. Upregulated Zeb1 mediates circ_K￾IAA1429 expression, leading to a robust driving force for HCC migra￾tion, invasion and EMT [93].
However, the performance of YTHDF2 in HCC is more complicated,
as shown above. YTHDF2 can work as both a molecular ‘rheostat’ and an
‘accelerator’, which depends on the mRNAs it processes. When its binds
to interleukin 11 (IL11)/serpin family E member 2 (SERPINE2) or EGFR,
YTHDF2 may act as a tumor suppressor [78,79]. In contrast, when
YTHDF2 recognizes OCT4 mRNA, it promotes HCC development and
cancer metastasis [82]. In addition, there are several other studies
showing that YTHDF2 has the potential to participate in HCC-related
phenotypes, such as proliferation and migration [80] and immune cell
infiltration [81], but further exploration is needed to determine the
specific regulatory mechanisms.
8. YTH proteins in lung cancer
Lung cancer is a molecularly heterogeneous disease [111]. Under￾standing the molecular biology of lung cancer is helpful for finding
promising strategies for early prognosis and treatment. Lung cancer is
classified into two types: NSCLC and small-cell lung cancer (SCLC).
NSCLC is the most common type, of which lung adenocarcinoma (LUAD)
is the most common subtype. Recently, METTL3 was identified as a
potential therapeutic target for patients with lung cancer as it promotes
the translation of oncogenes [112,113]. The functions of m6
A readers in
lung cancer remain largely unknown; the possible functions are dis￾cussed below.
The YAP signaling pathway plays a critical role in lung cancer,
including in tumorigenesis, aggressiveness, metastasis, and resistance to
drug treatment [114]. As a central component of the YAP signaling
pathway, YTHDF1 is recruited to m6
A-modified YAP mRNA, inducing
NSCLC drug resistance and metastasis by promoting YAP translation
[51,52]. Another m6
A target, PRPF6, screened by LUAD TCGA dataset
analysis, was shown to be positively expressed with YTHDF1. In this
study, the authors found that YTHDF1-dependent PRPF6 m6
A methyl￾ation is a key regulator of ATTM-induced anticancer effects. The
mechanism mediated by the m6
A-PRPF6-YTHDF1 axis indicates an op￾portunity for overcoming the side effects caused by ATTM therapy by
scavenging H2S [53]. Consistently, according to different datasets from
the TCGA and Gene Expression Omnibus (GEO), YTHDF1 is overex￾pressed in LUAD patients versus normal controls [115]. In addition,
YTHDF1, together with 5 other m6
A-related genes, was screened to build
a risk scoring signature that was strongly related to pathological stage,
sex and overall survival, indicating that YTHDF1 has good predictive
value in LAUD [56]. Additionally, m6
A modification was found to
participate in lung cancer cell metabolism via its reader YTHDF2 [85].
In this study, upregulated YTHDF2 bound to 6-phosphogluconate dehy￾drogenase (6PGD) and promoted 6PGD mRNA translation, indicating
that YTHDF2 is a lung cancer promoter. IGF2BPs are also detected
abnormally upregulated in LAUD tissue [103]. After irradiation, m6
level of VANGL1 is upregulated, as well as the VANGL1 mRNA stability
regulated by IGF2BP2/3, suggesting a regulatory role of IGF2BPs in
LUAD radio resistance [104].
Resistance to hypoxia-induced apoptosis, leading to distinctive
hypoxia adaption in de novo lung adenocarcinomas (ADCs), has been an
inevitable barrier leading to poor clinical outcomes of NSCLC treatment.
The search for more specific hallmarks and treatments in both ADC and
hypoxia-adapted NSCLC has become necessary and urgent. In the two
different progressions of NSCLC, YTHDF1 behaves in completely distinct
manners and provides us with new insights into cancer biology [54]. In
ADC, YTHDF1 deficiency impedes cancer progression by inhibiting
NSCLC cell proliferation and xenograft tumor formation through regu￾lating the translation activity of cyclin proteins. However, lower
expression of YTHDF1 is correlated with a worse clinical outcome
Table 1 (continued )
Cancer Expression Targets and Mechanism Role Reference
Upregulated Not mentioned. Positive prognostic target [96]
Prostate cancer Unknown Mediates Cd44v5-Luc splicing. Positive therapeutic target
YTHDC2 Colon cancer Upregulated Promotes translation of HIF-1α and
Potential prognostic signature [98]
Lung adenocarcinoma Downregulated Promotes SLC7A11 mRNA decay. Negative prognostic signature
Negative prognostic signature
Downregulated Not mentioned. [100]
IGF2BPs Breast cancer Unknown Promotes CERS6 mRNA stability. Potential therapeutic
Gastric cancer Upregulated Promotes HDGF mRNA stability. Potential prognostic
Lung cancer Upregulated Not mentioned. Positive prognostic signature [103]
Unknown Enhances VANGL1 mRNA stability. Potential therapeutic target [104]
Colorectal cancer Upregulated Prevents SOX2 mRNA degradation. Potential biomarker
B. Han et al.
Cancer Letters 518 (2021) 256–265
because of the resistance to cisplatin treatment in cancerous cells.
Depletion of YTHDF1 in hypoxic solid tumors makes cancerous cells
more resistant to cisplatin-dependent chemotherapy by regulating the
Keap1-Nrf2-AKR1C1 axis. In contrast, YTHDC2 is frequently suppressed
in LUAD [99,100]. Mouse model studies have shown that YTHDC2
preferentially binds to SLC7A11 mRNA and decreases tumorigenesis by
suppressing cystine uptake and blocking the downstream antioxidant
program [99].
9. YTH proteins in other cancers
The mRNAs recognized by YTH domain-containing proteins largely
determine their roles in the progression of specific cancers. In oral
squamous cell carcinoma, c-Myc is a direct YTHDF1 target gene and is
responsible for the acceleration of tumor growth [65]. The negative p53
regulators YY1 and MDM2 are targets stimulated by YTHDF2 to promote
human keratinocyte transformation in arsenic carcinogenesis [116]. In
ocular melanoma, YTHDF1 inhibits the progression of both uveal and
Fig. 3. Deregulation of m6
A reader proteins in human cancers.
A comprehensive overview of m6
A readers in human carcinogenesis, including proliferation, migration, invasion, metastasis, and chemoresistance regulation. These
readers specifically identify m6
A-modified mRNAs and subsequently regulate critical signaling pathways in the pathogenesis of cancers. Red box line indicates
upregulated expression and oncogenic functions. Blue line indicates downregulated expression and tumor suppresive functions. Black line indicates contradicted
roles within different studies. Dashed gray line indicates unaffected or unknown roles.
B. Han et al.
Cancer Letters 518 (2021) 256–265
conjunctival melanoma by promoting the translation of the tumor sup￾pressor HINT2 [58]. Notably, in addition to being recognized by
YTHDF3 in CRC, the tumor suppressor GAS is also identified by YTHDF2
in cervical cancer and acts as a critical molecule for cervical cancer
progression [72]. YTHDF2 also binds to FOXC2, TNFRSF1B, PER1, and
MOB3B in gastric cancer, AML, pancreatic cancer and prostate cancer,
respectively, providing similar insights into the underlying mechanisms
of carcinogenesis induced by RNA degradation [74,83,87,88]. In glio￾blastoma (GBM), despite different target transcripts, YTHDF1/2 and
YTHDC1 display similar function on GBM growth and progression,
indicating positive prognostic and therapeutic prospects of these readers
Studies have also indicated that more than one individual transcript
participates in m6
A reader-mediated effects in cancers. In ovarian cancer
and Merkel cell carcinoma, YTHDF1 augments m6
A-modified EIF3C
translation and concomitantly increases the global translational output,
thus facilitating tumorigenesis and cancer metastasis [60,67]. Addi￾tionally, YTHDF1 has been verified to bind to m6
A-modified PDK4 or
HK2 and promote cancer cell metabolic processes, such as glycolysis or
the Warburg effect in cervical cancer, which suggests that YTHDF1
could be a promising therapeutic target [62,63]. Similarly, a group of
transcripts encoding lysosomal proteases in dendritic cells are methyl￾ated and then recognized by YTHDF1. Deletion of YTHDF1 markedly
inhibits these cathepsins, thus enhancing the antitumor response of
antigen-specific CD8+ T cells [117]. In bladder cancer, SETD7 and KLF4
were both identified as direct targets of YTHDF2 through transcriptome
sequencing and confirmed with methylated RNA immunoprecipitation
(MeRIP)-RT-qPCR [71].
In addition, other studies have indicated a positive correlation be￾tween YTHDF1 expression and cancer development, but there is a lack of
mechanistic evidence in abdominal aortic aneurysm [118] and head and
neck squamous cell carcinoma [119]. Likewise, low expression of
YTHDC2 is significantly associated with worse overall survival in lung
cancer patients. However, the potential RNAs that interact with
YTHDC2 still need to be explored [100]. Further research is required to
decipher the specific targets of m6
A readers in these cancers, which may
contribute to the understanding of their clinical significance and po￾tential applications.
10. Conclusions and future perspectives
In this review, we summarized nearly all the recent findings on YTH
domain-containing proteins in cancers. Dysregulation of m6
A readers in
cancer tissues results in abnormal mRNA metabolism of oncogenes and
tumor suppressors, leading to the acceleration or delay of cancer
development (Fig. 3). However, our understanding of how YTH proteins
contribute to these processes remains incomplete. It is essential to
identify the intrinsic and extrinsic signals that regulate the recruitment
of YTH proteins to m6
A-modified mRNAs and to identify these tran￾scripts in a specific biological environment. In addition, the mechanisms
that control the expression and activities of YTH proteins remain largely
unknown. Therefore, future elucidation of the accurate roles of YTH
proteins in regulating gene expression in cancers with new tools and
methods is needed.
The crucial role of m6
A readers in cancer initiation and progression
provides potential targets for the treatment of cancers. Indeed, inhibi￾tion of YTHDF1 showed therapeutic potential alone or in combination
with anti-PD-L1 immunotherapy in CRC [39,117]. However,
small-molecule agents targeting YTH proteins, by blocking their inter￾action with m6
A-modified mRNAs or other regulatory proteins, remain
to be identified or developed. These small molecules might serve as a
potential way to inhibit dysregulated mRNA metabolism by YTH pro￾teins in cancer. On the other hand, targeted m6
A editors and readers
based on CRISPR/dCas system have been recently developed [30–33].
Taking advantage of these tools, manipulating the oncogenic or tumor
suppressive mRNAs of interest with specific editors or readers could be
achieved to modulate cancer cell characteristics. Of note, Li et al. have
used dCas13b-ALKBH5 to demethylate m6
A modifications on oncogene
transcripts such as EGFR and MYC, resulting in altered cancer cell pro￾liferation in vitro [31]. However, whether these tools could be applied to
cancer treatment remains to be explored.
Author contributions
All the authors summerized and discussed. B.H. and X.G. wrote the
Declaration of competing interest
The authors declare that they have no conflict of interest.
This work was supported by grants from National Natural Science
Foundation of China (82073110 and 81672847 to X.G.), Zhejiang Youth
Talent Support Program (ZJWR0308085 to X.G.), Zhejiang Provincial
Natural Science Foundation of China (LQ19C050004 to S.W.), and
Guangdong Provincial Science and Technology Project
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