METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway

Sep 24, 2026

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METTL3-mediated m6A modification drives colorectal cancer progression via a dual regulatory mechanism on the JAK1/STAT3 axis. Upregulated METTL3 deposits m6A on the JAK1 3’ untranslated region to promote YTHDF1-dependent JAK1 translation. Separately, METTL3 relocates to the STAT3 promoter and cooperates with NF-κB to enhance STAT3 transcription independently of its methyltransferase activity. Elevated JAK1 and STAT3 activate p-STAT3 signaling and increase VEGFA and CCND1 expression, promoting proliferation and metastasis in vitro and in vivo.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Roles of m6A writers, erasers, and readers

m6A involvement in disease and cancer

Prior evidence for METTL3 in colorectal cancer

Results

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway Yuechao Sun1,4, Weipeng Gong2,4 and Song Zhang 3 ✉ © The Author(s) 2023 | | | | | --- | --- | --- | | | The role of METTL3-mediated N6-methyladenosine (m6A) modiﬁcation has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal cancer exerted both methyltransferase activity-dependent and -independent functions in gene regulation. METTL3 deposited m6A on the 3’ untranslated region of the JAK1 transcript to promote JAK1 translation relying on YTHDF1 recognition. Besides, METTL3 was redistributed to the STAT3 promoter and worked in concert with NF-κB to facilitate STAT3 transcription, which was achieved independently on METTL3 methyltransferase activity. The increased JAK1 and STAT3 corporately contributed to the activation of the p-STAT3 signaling pathway and further upregulated downstream effectors expressions, including VEGFA and CCND1, which ﬁnally resulted in enhanced cancer cell proliferation and metastasis in vitro and in vivo. Collectively, our study revealed the unappreciated dual role of METTL3 as an m6A writer and a transcription regulator, which | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | worked together in the same signaling pathway to drive colorectal cancer malignancy. | | | | | Cell Death and Disease (2023)14:765; [https://doi.org/10.1038/s41419-023-06287-w](https://doi.org/10.1038/s41419-023-06287-w) | | | | | | INTRODUCTION Among over 150 known RNA modiﬁcations, N6-methyladenosine (m6A) is the most prevalent internal decoration of mammalian messenger RNA, accounting for more than 80% of RNA modiﬁcations [1]. Since fat mass and obesity-associated protein (FTO) were identiﬁed with the ability of demethylase [2], the process of m6A modiﬁcation has been characterized by dynamics and reversibility. Methyltransferase-like 3 (METTL3), METTL14, WT1-associated protein (WTAP) and other accessory proteins constitute heterocomplex to function as m6A methyltransferases (writers) in mammalian cells [3] . Among them, METTL3 serves as the core catalytic subunit of the methyltransferase complex [4] . Moreover, AlkB Homolog 5 (ALKBH5) and FTO are reported as RNA demethylases that act as erasers for recognizing different m6A sites [5] . In addition to writers and erasers, the fate of the RNA transcripts harboring m6A modiﬁcations is usually determined by the reader proteins that are in charge of decoding m6A markers. The list of m6A reader proteins includes the YTH domain family proteins (YTHDF1/2/3, YTHDC1/2) [6], the insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1/2/3) [7], and the heterogeneous nuclear ribonucleoproteins (hnRNPA2B1, hnRNPG) [8, 9], etc. It is becoming clear that almost all aspects of RNA metabolism, from transcription, splicing, export, and translation to degradation, are regulated by different m6A reader machinery [10] . Beneﬁting from the development of anti-m6A immunoprecipitation and high-throughput sequencing, the understanding of biological functions of m6A modiﬁcation in mRNA has been widely expanded in recent years. It has been reported that m6A modiﬁcation is implicated in a series of biological processes, including stem cell self-renewal and differentiation [11], DNA damage repair [12], immunoregulation [13], sex determination [14], etc. Except for normal physiological activity, m6A has also been linked to the pathogenesis of several diseases, including cancer. In leukemia, FTO inhibition sensitizes leukemia cells to T-cell cytotoxicity and overcomes immune evasion [15] . ALKBH5 is required for the development and maintenance of leukemia stem cells by post-transcriptional regulation of several oncoge

FAQs

How does METTL3 increase JAK1 expression in colorectal cancer?

METTL3 deposits m6A on the JAK1 3’ untranslated region, promoting YTHDF1-recognition-dependent JAK1 translation.

How does METTL3 enhance STAT3 transcription?

METTL3 is redistributed to the STAT3 promoter and works with NF-κB to facilitate STAT3 transcription independently of methyltransferase activity.

What are the downstream effects of activating JAK1/STAT3 signaling?

Activated p-STAT3 increases downstream effectors such as VEGFA and CCND1, resulting in enhanced cancer cell proliferation and metastasis in vitro and in vivo.

Sep 24, 2026

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