TRMT6-mediated tRNA m1A modification serves as a translational checkpoint of histone biosynthesis and facilitates colorectal cancer progression [Ribo]

Reprogramming of mRNA translation drives malignant transformation and cancer development. Recently, increasing studies have demonstrated that tRNA modification emerges as a critical regulator of translational reprogramming; however, its function in cancers remains largely elusive. Herein, we identify the oncogenic role of tRNA N1-methyladenosine (m1A) modification in colorectal cancer (CRC). Targeting m1A methyltransferase TRMT6 in CRC cells decreases the abundance of a specific subset of tRNAs (e.g., tRNA-Arg-ACG-1-1, tRNA-Lys-TTT-1-1) and impairs histone mRNA translation in a codon-biased manner, thus restricting histone biosynthesis and cell cycle progression. We further demonstrate that the combination of TRMT6 inhibition and CDK4/6 inhibition shows a stronger anti-cancer effect on CRC cells by synergistically inhibit histone biosynthesis. Collectively, our study reveals that tRNA m1A modification acts as a translational checkpoint of histone biosynthesis and promotes CRC progression, providing new insights for the development of efficient therapeutic strategies against CRC. Comparative ribosome footprinting profiling analysis of RKO cells and its KD derivative (shTRMT6).