ZDHHC12 palmitoylates HDAC8 and promotes the development of hepatocellular carcinoma associated with a diet high in saturated fatty acids

Excessive intake of saturated fatty acids (SFAs), which are prevalent in diets high in fried foods and red meat, poses a significant threat for hepatocellular carcinoma (HCC). Herein, we found via Mendelian randomization (MR) analysis that SFAs could be one of the factors leading to HCC. However, the role and associated mechanism of SFAs in HCC progression remain poorly understood. Palmitic acid (PA) is the most common type of SFA. We therefore chose PA as an example of SFAs for our study. We identified zinc finger DHHC-type palmitoyltransferase 12 (ZDHHC12) as a key protein involved in the promotion of HCC progression by PA, which was accomplished by maintaining the stability of the recognized HCC-promoting gene histone deacetylase 8 (HDAC8). Mechanistically, supplementation with PA led to the upregulation of ZDHHC12 expression via activation of the transcription factor SWI/SNF-related BAF chromatin remodeling complex subunit ATPase 4 (SMARCA4). ZDHHC12 mediated the palmitoylation of HDAC8 at cysteine 244, thereby preventing the lysosomal degradation of HDAC8, which promoted the progression of HCC. In conclusion, this study revealed that ZDHHC12 was a key protein in palmitic acid-mediated HCC progression and that targeting HDAC8 could inhibit this process. These findings offer a potential therapeutic strategy for HCC patients with a high intake of saturated fatty acids, especially palmitic acid.