In this study, through a systematic analysis of gene transcription and DNA methylation of cancer cell lines that are sensitive or resistant to OXPHOS inhibition, we identified that SAM‐regulated enzyme NNMT and SAM consumer DNMT1 function together in maintaining a state of cancer cells for OXPHOS dependency in cultured cancer cells, mouse tumor xenografts, and colorectal adenomas (CRAs) in patients. Here, NNMT is linked to neoplasm.