METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer

作者：Huarong Chen, Yasi Pan, Qiming Zhou, Cong Liang, Chi-Chun Wong, Yunfei Zhou, Dan Huang, Weixin Liu, Jianning Zhai, Hongyan Gou, Hao Su, Xiaoting Zhang, Hongzhi Xu, Yifei Wang, Wei Kang, William Ka Kei Wu, Jun Yu · 发表于：Gastroenterology · 年份：2022 · DOI：10.1053/j.gastro.2022.06.024 · 被引用次数：300 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Ubiquitin and proteasome pathways

Background & Aims N 6 -Methyladenosine (m 6 A) is the most prevalent RNA modification and recognized as an important epitranscriptomic mechanism in colorectal cancer (CRC). We aimed to exploit whether and how tumor-intrinsic m 6 A modification driven by methyltransferase like 3 (METTL3) can dictate the immune landscape of CRC. Methods Mettl3 knockout mice, CD34 + humanized mice, and different syngeneic mice models were used. Immune cell composition and cytokine level were analyzed by flow cytometry and Cytokine 23-Plex immunoassay, respectively. M 6 A sequencing and RNA sequencing were performed to identify downstream targets and pathways of METTL3. Human CRC specimens (n = 176) were used to evaluate correlation between METTL3 expression and myeloid-derived suppressor cell (MDSC) infiltration. Results We demonstrated that silencing of METTL3 in CRC cells reduced MDSC accumulation to sustain activation and proliferation of CD4 + and CD8 + T cells, and eventually suppressed CRC in Apc Min/+ Mettl3 +/− mice, CD34 + humanized mice, and syngeneic mice models. Mechanistically, METTL3 activated the m 6 A-BHLHE41-CXCL1 axis by analysis of m 6 A sequencing, RNA sequencing, and cytokine arrays. METTL3 promoted BHLHE41 expression in an m 6 A-dependent manner, which subsequently induced CXCL1 transcription to enhance MDSC migration in vitro. However, the effect was negligible on BHLHE41 depletion, CXCL1 protein or CXCR2 inhibitor SB265610 administration, inferring that METTL3 promotes MD...