METTL16 promotes colorectal cancer progression and CD8⁺ T cell function through BCAT1-dependent branched-chain amino acid metabolism.

Authors

Yanyan Hu, Shengying Li, Minjing Zhu, Xuedan Lin, Chaoju Gong, Zejun Fang

Published in

Medical oncology (Northwood, London, England). Volume 43. Issue 11. Sep 25, 2026. Epub Sep 25, 2026.

Abstract

This study aims to investigate whether Methyl-Transferase-Like Protein 16 (METTL16) promotes colorectal cancer (CRC) progression through regulating branched-chain amino acid (BCAA) transaminase 1 (BCAT1)-mediated metabolism to modulate CD8⁺T cell-mediated anti-tumor immunity. METTL16 levels were measured in clinical CRC samples and cell models using IHC, qPCR and western blot. Functional assays (CCK-8, EdU, wound healing, transwell) were performed to evaluate the impact of METTL16 knockdown on CRC cell behaviors. A co-culture system with CD8⁺T cells was established to assess immune evasion mechanisms. RIP, MeRIP, and mRNA stability assays were conducted to explore METTL16's regulation of BCAT1 via m6A modification. Metabolomics analysis using LC-MS/MS quantified branched-chain amino acids (BCAAs). In vivo experiments utilized a xenograft mouse model to validate findings. METTL16 was elevated in CRC. Knockdown of METTL16 suppressed malignant phenotype of CRC cell, while enhancing CD8⁺T cell proliferation and cytotoxic molecule secretion (IFN-γ, IL-2, and GzmB). METTL16 regulated BCAT1 expression through m6A-dependent mRNA stabilization, promoting BCAAs metabolism. Rescue experiments demonstrated that BCAT1 overexpression reversed the regulation of METTL16 knockdown on tumor cell malignancy and CD8⁺ T cell responses. In vivo, METTL16 depletion inhibited tumor growth, reduced Ki-67 expression, and enhanced CD8⁺T cell infiltration and effector molecule levels. METTL16 drives CRC progression by promoting BCAT1-mediated BCAAs metabolism and facilitating immune evasion through suppression of CD8⁺T cell function.

PMID:
42789224
Bibliographic data and abstract were imported from PubMed on 26 Sep 2026.

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