Integrated functional genomics-identified LYRM4 promotes fumarate accumulation and hepatocellular carcinoma...

Multiple risk factors for HCC have been identified, however, not all individuals exposed to these factors will develop HCC, suggesting that genetic predisposition also contributes to hepatocarcinogenesis. Despite the identification of numerous single-nucleotide polymorphisms (SNPs) in HCC risk loci and several protein-coding susceptibility genes through genome-wide association studies (GWAS), the potential mechanisms are still not fully understood. In this study, we used The Updated Integrative Functional Genomics Approach (TUIFGA) method to investigate functional causal genetic variants in HCC. We identified one SNP rs399283 associated with HCC risk, which locates in CREB1 binding motif of the LYRM4 intronic enhancer. The rs399283 genetic variation may affect the binding of CREB1 to the enhancer of the oncogene LYRM4 in HCC, leading to allele-specific gene expression changes. Mechanistically, elevated levels of LYRM4 enhance the enzymatic activities of succinate dehydrogenase (SDH), thereby promoting fumarate accumulation in cells and playing a key role in HCC tumorigenesis. Our results offer valuable insights into the genetic complexity of HCC and emphasize the significant potential of fumarate regulation as a novel approach for cancer therapy.