Abstract
BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates are steadily on the rise, which brings significant public health concern worldwide, especially in China. Methyltransferase-like 7 A (METTL7A), a member of the methyltransferase-like family, is associated with various cancers including CRC. Notably, CRC progression is closely linked to metabolic reprogramming. However, its precise role in CRC, particularly metabolic reprogramming of CRC, remains unclear. METHODS: METTL7A was identified as a pivotal gene closely associated with CRC by bioinformatics analyses. Through a series of cellular functional assays and several animal experiments, such as in situ tumor and spontaneous tumor in C57BL/6 mice, the role of METTL7A in the development of colorectal cancer was evaluated. Transcriptomics and proteomics were used to analyze the effects of METTL7A on the expression of numerous genes, especially those involved in metabolic processes including cholesterol synthesis pathway within CRC cells. Western-blotting, co-immunoprecipitation and immunofluorescence were used to elucidate the relationship of METTL7A and the cholesterol metabolic pathway. RESULTS: METTL7A exhibited low expression in CRC cell lines and CRC tissues and it was demonstrated to function as a tumor suppressor in CRC. Transcriptomic and proteomic analyses indicated that METTL7A affects genes related to the cholesterol metabolism pathway. METTL7A was further proven to directly bind to Sterol Regulatory Element-Binding Protein1 (SREBP1) and SREBP Cleavage-Activating Protein (SCAP), hindering the nuclear translocation of SREBP1 and thereby reducing intracellular cholesterol content. CONCLUSIONS: This study provides valuable insights into the role of METTL7A in CRC and its impact on metabolic reprogramming, particularly cholesterol synthesis, and identifies METTL7A as a potential therapeutic target of CRC.