Novel role of general transcript factor IIH subunit 2 (GTF2H2) in the development and sex disparity of hepatocellular carcinoma

Sex disparity is a hepatocellular carcinoma (HCC) hallmark, demonstrating aggressiveness and mortality more frequently in men than in women. However, the components of its basis remain largely unknown. It was identified in HCC frequent loss of heterozygosity of general transcript factor IIH subunit 2 (GTF2H2), a potential estrogen pathway gene. GTF2H2 functions in nucleotide excision repair (NER) and basal transcription, but the function of GTF2H2 in cancer has not been described in depth. Here, it was identified that GTF2H2 inhibited growth and invasive mobility and induced apoptosis of HCC cells, which was up-regulated by estrogen-dependent estrogen receptor alpha (ERα) signaling. Mechanistically, in vitro estrogen-treated HCC models with GTF2H2 knockdown and over-expression showed estrogen-regulated GTF2H2 promoted NER of HCC genomic DNA and inhibited cell cycle progression, and down-regulated PAM/NF-κB pathway. Xenografted HCC mice models showed higher tumor progression of HCC with low GTF2H2 expression in ovariectomized female mice or male mice, but could be rescued by GTF2H2 over-expression, which was also observed in spontaneous tumor mice models. Clinical association analysis of HCC cases showed GTF2H2 expression was higher in female HCC, with correlation positively with ERα expression. Taken together, the estrogen-regulated GTF2H2 may be involved in the development and sex disparity of HCC by maintaining NER-related genomic stability and affecting PAM/NF-κB signaling pathway.