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Abstract The widespread presence of N1-methyladenosine (m1A) modifications controls RNA metabolism and is pivotal to fundamental biological processes. However, the understanding of RNA m1A involved in cancer is still minimal. Here we reported the oncogenic role and the therapeutic targeting of RNA m1A methyltransferase TRMT61A in colorectal cancer (CRC). We observed consistent elevation of TRMT61A expression and RNA m1A levels in primary CRC tissues, which was significantly associated with poor patient survival in two independent cohorts (both P. 001). CRISPR/Cas9 screenings revealed that TRMT61A is the most essential gene among m1A regulators. TRMT61A facilitates the growth and metastasis of CRC cells by increasing the stability of mRNA of crucial targets, such as ONECUT2, which leads to the activation of MAPK/ERK signaling in an m1A-dependent manner. Notably, depletion of ONECUT2 or inhibition of MAPK/ERK could abrogate the tumor-promoting role of TRMT61A, implying that TRMT61A induces ONECUT2-MAPK/ERK axis to facilitate CRC. Inhibiting TRMT61A with nanoparticle-encapsulated siTRMT61A or our recently identified small molecule compound PGG shows promising anti-CRC effects in vitro and in vivo. Together, our study reveals the promoting role of TRMT61A-induced m1A modification in MAPK/ERK signaling and highlights the potential of targeting TRMT61A as a promising therapeutic approach in CRC treatment. Citation Format: Xiaoting Zhang, Na Qin, Fenfen Ji, Hao Su, Hongyan Chen, Haiyun Shang, Huarong Chen. RNA m1A methyltransferase TRMT61A induces MAPK/ERK signaling and is a therapeutic target in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4597.
Zhang et al. (Fri,) studied this question.