TATA-box binding protein-associated factor 2 (TAF2) in hepatocyte survival and tumorigenesis.

[BACKGROUND AND AIMS] Chromosome 8q amplification is a frequent event in cancers, including HCC. TATA-box binding protein associated factor 2 (TAF2), a component of transcription factor IID (TFIID) residing in 8q24.12, is amplified in HCC. As yet, a potential oncogenic function of TAF2 in HCC has not been documented.

[APPROACH AND RESULTS] We identified TAF2 mRNA and protein overexpression in human HCC cells and tissue samples, compared to their normal counterparts. A significant negative correlation between TAF2 levels and the overall survival of HCC patients was observed. The role of TAF2 in HCC regulation was examined using a hepatocyte-specific conditional knockout mouse (Taf2 ΔHEP ), TAF2 knockdown and overexpression in human HCC cells, and TAF2 overexpression in mouse liver by hydrodynamic approach. As a core component of basal transcription machinery, TAF2 is required for hepatocyte survival. As such, in Taf2 ΔHEP mice, there was hepatocyte death and compensatory proliferation, contributing to an inflammatory/fibrotic milieu favoring HCC. Accordingly, N-nitrosodiethylamine (DEN)/high-fat high-sugar diet-induced HCC was robustly augmented in Taf2 ΔHEP mice compared to their wild-type littermates. TAF2 overexpression in mouse liver did not lead to tumor development, but significantly augmented HCC that was induced by overexpression of the driver oncogene MYC. TAF2 augmented cancer hallmarks in human HCC cells by binding to the promoters of tumor-promoting genes and non-coding RNAs and regulating their transcription.

[CONCLUSION] TAF2 plays a unique and central role in hepatocyte survival and tumorigenesis.