2. Academic Validation
  3. Transcriptional regulator CTR9 promotes hepatocellular carcinoma progression and metastasis via increasing PEG10 transcriptional activity

Transcriptional regulator CTR9 promotes hepatocellular carcinoma progression and metastasis via increasing PEG10 transcriptional activity

  • Acta Pharmacol Sin. 2022 Aug;43(8):2109-2118. doi: 10.1038/s41401-021-00812-3.
Bin Zhang  # 1 2,  Zhi-Yi Liu  # 1 2,  Rui Wu  # 1 2,  Cheng-Ming Zhang 1 2,  Kuan Cao 1 2,  Wen-Gang Shan 1 2,  Zhen Liu 1 2,  Ming Ji 1 2,  Zi-Lu Tian 1 2,  Gautam Sethi 3,  Heng-Liang Shi 4 5 6,  Ren-Hao Wang 7 8
Affiliations

Affiliations

  • 1 Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221004, China.
  • 2 Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China.
  • 3 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore. phcgs@nus.edu.sg.
  • 4 Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221004, China. shl@xzhmu.edu.cn.
  • 5 Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China. shl@xzhmu.edu.cn.
  • 6 Central Laboratory, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China. shl@xzhmu.edu.cn.
  • 7 Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221004, China. wangrenhao@xzhmu.edu.cn.
  • 8 Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221004, China. wangrenhao@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 34876700 DOI: 10.1038/s41401-021-00812-3
Abstract

Cln Three Requiring 9 (CTR9), a scaffold protein of the polymerase-associated factor-1 (PAF1) complex (PAF1c), is primarily localized in the nucleus of cells. Recent studies show that CTR9 plays essential roles in the development of various human cancers and their occurrence; however, its regulatory roles and precise mechanisms in hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the roles of CTR9 using in vitro assays and a xenograft mouse model. We found that CTR9 protein is upregulated in tumor tissues from HCC patients. Knockdown of CTR9 substantially reduced HCC cell proliferation, invasion, and migration, whereas its overexpression promoted these activities. In addition, in vitro results revealed that CTR9 silencing dramatically increased cell cycle regulators, p21 and p27, but markedly decreased Matrix Metalloproteinases, MMP2 and MMP9, with these outcomes reversed upon CTR9 overexpression. Furthermore, the underlying molecular mechanism suggests that CTR9 promoted the oncogene paternally expressed gene 10 (PEG10) transcription via its promoter region. Finally, the oncogenic roles of CTR9 were confirmed in a xenograft mouse model. This study confirms that CTR9, an oncoprotein that promotes HCC cell proliferation, invasion, and migration, increases tumor growth in a xenograft mouse model. CTR9 could be a novel therapeutic target. Further investigation is warranted to verify CTR9 potential in novel therapies for HCC.

Keywords

Cln Three Requiring 9; cell cycle; hepatocellular carcinoma; matrix metalloproteinase; paternally expressed gene 10.

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