Tripartite motif-containing protein 11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome-mediated degradation of pleckstrin homology domain leucine-rich repeats protein phosphatase 1.

Abstract

BACKGROUND AND AIMS:

HCC is one of the main types of primary liver cancer, with high morbidity and mortality and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC remain open for study.

APPROACH AND RESULTS:

Through clinical analysis, we found that the expression of TRIM11 was up-regulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade, and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with pleckstrin homology domain leucine-rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1 and thus promoted activation of the protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function.

CONCLUSIONS:

Our study confirmed that TRIM11 plays an oncogenic role in HCC through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of HCC.

• Authors: Juan Yang, Jianming Ye, Tengfei Ma, Fangfang Tang, Li Huang, Zhen Liu, Song Tian, Xu Cheng, Li Zhang, Zhenli Guo, Fuping Tu, Miao He, Xueming Xu, Xiaojuan Lu, Yanyang Wu, Xiaoli Zeng, Jiahua Zou, Xiangcai Wang, Weijie Peng, Peng Zhang
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 76 Issue 3 Pg. 612-629 (09 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34767673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Association for the Study of Liver Diseases.

Chemical References

• Tripartite Motif Proteins
• Ubiquitin
• TRIM11 protein, human
• Ubiquitin-Protein Ligases
• Proto-Oncogene Proteins c-akt
• Protein Phosphatase 1
• Proteasome Endopeptidase Complex
• Leucine

Topics

• Carcinogenesis (genetics)
• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Leucine
• Liver Neoplasms (pathology)
• Pleckstrin Homology Domains
• Proteasome Endopeptidase Complex (metabolism)
• Protein Phosphatase 1 (genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• Tripartite Motif Proteins (genetics, metabolism)
• Ubiquitin
• Ubiquitin-Protein Ligases (metabolism)