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Activating transcription factor 2 (ATF2) is a tumor driver gene implicated in several human malignancies. This study aimed to determine the roles of ATF2 and its related molecules in the tumorigenesis of hepatocellular carcinoma (HCC). According to the Pan‐cancer bioinformatics system, ATF2 is highly expressed in HCC. An increase in the expression of ATF2 was identified in clinically collected tumor tissues and procured HCC cells. The silencing of ATF2 reduced the viability, colony formation, invasion, and death resistance of HepG2 and SNU‐398 cells in vitro. ATF2 promoted the transcription of Wolf‐Hirschhorn syndrome candidate 1 (WHSC1) by binding to its promoter. WHSC1 further increased the expression of DNA topoisomerase II alpha (TOP2A) in HCC by inducing the dimethylation of histone H3 lysine 36 (H3K36me2) in the TOP2A promoter region. TOP2A activated the oncogenic PI3K/AKT signaling pathway. Further overexpression of WHSC1 activated the TOP2A/PI3K/AKT axis and restored the malignant behaviors of HCC cells suppressed by ATF2 silencing in vitro. In summary, this study demonstrated that, depending on WHSC1, ATF2 can activate the TOP2A/PI3K/AKT signaling cascade to promote the tumorigenesis of HCC. ATF2, WHSC1, and TOP2A may serve as potential targets in managing HCC. [ABSTRACT FROM AUTHOR]

Lysine demethylase 5C (KDM5C) is a member of the KDM family of demethylases and has been reported as a cancer driver. This study aimed to probe the function of KDM5C in the development of liver hepatocellular carcinoma (LIHC) and the molecules of action. According to data from publicly accessible bioinformatic databases, KDM5C is highly expressed in LIHC and associated with poor patient prognosis. High expression of KDM5C was detected in acquired LIHC cell lines. Downregulation of KDM5C weakened proliferation, migration, invasiveness, and resistance to death of the LIHC cells in vitro, and it reduced growth of the xenograft tumors in nude mice. Inter‐alpha‐trypsin inhibitor heavy chain 1 (ITIH1) was predicted as a downstream gene negatively regulated by KDM5C. KDM5C‐regulated H3K4me1 modification at the promoter region of ITIH1, inducing its transcriptional inactivation. Further downregulation of ITIH1 in cancer cells blocked the functions of KDM5C silencing and restored the malignant behaviors of LIHC cells. The activity of the PI3K/AKT signaling was decreased following KDM5C downregulation but recovered upon ITIH1 silencing. In conclusion, this study suggested that KDM5C epigenetically reduces ITIH1 and activates the PI3K/AKT signaling pathway to promote LIHC progression. [ABSTRACT FROM AUTHOR]