Cancer‐Type‐Specific <scp>DNA</scp> Methylation Is a Source of Vulnerability in Liver Cancer Cells

DNA methylation, a pivotal epigenetic mechanism, plays a critical role in various pathological conditions, including cancers. Notably, cancer-type-specific DNA methylation can be advantageous for survival only in specific environments while being disadvantageous in others. To investigate the role of cancer-type-specific methylation as a vulnerability in cancer cells, we bioinformatically profiled genome-wide DNA methylation in 1165 human cancer cell lines across 25 cancer types. The number of cancer-type-specific methylated cytosines varied significantly by organ, with exceptionally high numbers observed in blood cancers. A total of 73 genes were identified as potential liver cancer-specific methylation-silenced genes, and four genes, ASNS, NQO1, FXYD5, and BCAT2, were subjected to experimental further analysis. Silencing of BCAT2 was found to contribute to the vulnerability of liver cancer cells to BCAT1 inhibition by gabapentin. Additionally, the silencing of the other three genes also rendered liver cancer cells vulnerable under different environmental conditions. These findings enhance our understanding of the biological and clinical significance of DNA methylation and provide a basis for developing diagnostic markers for cancer. (169 words).