Activating transcription factor 2 promotes the progression of hepatocellular carcinoma by inducing the activation of the WHSC1-mediated TOP2A/PI3K/AKT axis.

Abstract

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.

• Authors: Zhong-Ming Bao, Dan Yao, Xu Qian, Hua-Guo Zhang, Ming Yang, Yun-Hu Guo, Lei Qin
• Journal: The Kaohsiung journal of medical sciences (Kaohsiung J Med Sci) Vol. 38 Issue 7 Pg. 662-674 (Jul 2022) ISSN: 2410-8650 [Electronic] China (Republic : 1949- )
• PMID: 35394699 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.

Chemical References

• ATF2 protein, human
• Activating Transcription Factor 2
• Repressor Proteins
• Histone-Lysine N-Methyltransferase
• NSD2 protein, human
• Proto-Oncogene Proteins c-akt
• DNA Topoisomerases, Type II

Topics

• Activating Transcription Factor 2 (genetics)
• Carcinogenesis (genetics)
• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• DNA Topoisomerases, Type II (genetics, metabolism)
• Histone-Lysine N-Methyltransferase (genetics, metabolism)
• Humans
• Liver Neoplasms (pathology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)