The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein.

Abstract

Aberrant Src kinase activity is known to be involved in a variety of human malignancies, whereas the regulatory mechanism of Src has not been completely clarified. Here, we demonstrated that tripartite motif containing 7 (TRIM7) directly interacted with Src, induced Lys48-linked polyubiquitination of Src and reduced the abundance of Src protein in hepatocellular carcinoma (HCC) cells. We further identified TRIM7 as a tumor suppressor in HCC cells through its negative modulation of the Src-mTORC1-S6K1 axis in vivo and in vitro in several HCC models. Moreover, we verified the dysregulated expression of TRIM7 in clinical liver cancer tissues and its negative correlation with Src protein in clinical HCC specimens. Overall, we demonstrated that TRIM7 suppressed HCC progression through its direct negative regulation of Src and modulation of the Src-mTORC1-S6K1 axis; thus, we provided a novel insight into the development of HCC and defined a promising therapeutic strategy for cancers with overactive Src by modulating TRIM7.

• Authors: Lihui Zhu, Chengyong Qin, Tao Li, Xiaomin Ma, Yumin Qiu, Yueke Lin, Dapeng Ma, Zhenzhi Qin, Caiyu Sun, Xuecheng Shen, Yunxue Zhao, Lihui Han
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 27 Issue 6 Pg. 1819-1831 (06 2020) ISSN: 1476-5403 [Electronic] England
• PMID: 31802035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tripartite Motif Proteins
• TRIM7 protein, human
• Ubiquitin-Protein Ligases
• src-Family Kinases

Topics

• Animals
• Carcinoma, Hepatocellular (metabolism)
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Hep G2 Cells
• Humans
• Liver Neoplasms (metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Protein Binding
• Tripartite Motif Proteins (physiology)
• Ubiquitin-Protein Ligases (physiology)
• src-Family Kinases (metabolism)