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E2F4/SETD1A axis-mediated METTL3 methylation promotes tumor immune evasion through impeding endogenous retroelements expression

ABSTRACT: Colorectal cancer (CRC) progression and recurrence persist as major clinical challenges despite standard therapies. Emerging evidence underscores that tumor relapse arises from crosstalk between malignant cells and the immunosuppressive microenvironment, yet the role of non-histone lysine methylation in this interplay remains unclear. Here, we identify di-methylation of lysine 513 (K513) on methyltransferase-like 3 (METTL3) as a key epigenetic modification associated with CRC progression and recurrence. Mechanistically, we reveal that SETD1A catalyzes METTL3 K513 methylation, enhancing its binding affinity to S-adenosylmethionine (SAM) and augmenting RNA m⁶A deposition. Strikingly, METTL3 methylation suppresses endogenous retroelements expression, leading to impaired type I interferon responses and tumor immune evasion. We further uncover a fluorouracil-induced E2F4/SETD1A/METTL3 regulatory axis, wherein E2F4 self-regulation activates SETD1A to drive METTL3 methylation. Targeting this axis through pharmacological inhibition of E2F4 or genetic disruption of METTL3 methylation synergizes with immune checkpoint blockade (ICB), significantly suppressing tumor growth. Our findings unveil a methylation-dependent regulatory mechanism that reshapes the tumor immune microenvironment, offering a novel therapeutic strategy for CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296929 | GEO | 2025/12/01

REPOSITORIES: GEO

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E2F4/SETD1A axis-mediated METTL3 methylation promotes tumor immune evasion through impeding endogenous retroelements expression

Project description:E2F4/SETD1A axis-mediated METTL3 methylation promotes tumor immune evasion through impeding endogenous retroelements expression

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Project description:SETD1A catalyzes methylation of histone 3 lysine 4 (H3K4) and plays a critical role in development of multiple cancers. The abrrent expression of SETD1A relates to poor prognosis of gastric cancer (GC) patients. Here, we revealed that SETD1A is required for GC cell proliferation. Rescue experiment showed catalytic function is not necessary for GC cell growth and gene expression, whereas a novel non-catalytic FLOS domain is indispensable. The CRISPR screening targeting SETD1A targets identified that TAF6 acts as a downstream target of SETD1A which is essential for GC cell survival. Both SETD1A and TAF6 are required for G1/S cell cycle progression in GC cells. Non-catalytic component of SETD1A regulating expression of TAF6 through coactivating with E2F4s. These results demonstrate that non-canonical roles of SETD1A in GC cell, which supplys a potential therapeutic opportunity for GC.

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Non-catalytic role of SETD1A promotes gastric cancer cell proliferation through the E2F4-TAF6 axis in the cell cycle (ChIP-seq)

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Project description:METTL14 (methyltransferase-like 14) is an RNA binding protein that partners with METTL3 to mediate N6-methyladenosine (m6A) methylation of mRNA. Recent studies identified a function for METTL3 in heterochromatin and transcription, but the role of METTL14 in these contexts remains unclear. Here we show that METTL14 binds and regulates mouse embryonic stem cell bivalent domains, which are marked with tri-methylation at lysine 27 of histone H3 (H3K27me3) and tri-methylation at lysine 4 of histone H3 (H3K4me3). Knockout of Mettl14 results in decreased H3K27me3 but increased H3K4me3 levels at bivalent regions, resulting in the resolution of the bivalency and in increased transcription. We demonstrate that bivalent domain regulation by METTL14 is independent of METTL3 or m6A modification. Instead, METTL14 enhances H3K27me3 and reduces H3K4me3 by interacting with and probably recruiting the histone 3 lysine 27 (H3K27) methyltransferase complex PRC2 and the histone 3 lysine 4 (H3K4) demethylases KDM5B to chromatin. Our findings identify a METTL3-independent function of METTL14, important for maintaining the bivalent domains in mESCs, thus revealing a new mechanism of bivalent domain regulation in mammals.

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