title: TRIM65 negatively regulates p53 through ubiquitination.
abstract: Tripartite-motif protein family member 65 (TRIM65) is an important protein involved in white matter lesion. However, the role of TRIM65 in human cancer remains less understood. Through the Cancer Genome Atlas (TCGA) gene alteration database, we found that TRIM65 is upregulated in a significant portion of non-small cell lung carcinoma (NSCLC) patients. Our cell growth assay revealed that TRIM65 overexpression promotes cell proliferation, while knockdown of TRIM65 displays opposite effect. Mechanistically, TRIM65 binds to p53, one of the most critical tumor suppressors, and serves as an E3 ligase toward p53. Consequently, TRIM65 inactivates p53 through facilitating p53 poly-ubiquitination and proteasome-mediated degradation. Notably, chemotherapeutic reagent cisplatin induction of p53 is markedly attenuated in response to ectopic expression of TRIM65. Cell growth inhibition by TRIM65 knockdown is more significant in p53 positive H460 than p53 negative H1299 cells, and knockdown of p53 in H460 cells also shows compromised cell growth inhibition by TRIM65 knockdown, indicating that p53 is required, at least in part, for TRIM65 function. Our findings demonstrate TRIM65 as a potential oncogenic protein, highly likely through p53 inactivation, and provide insight into development of novel approaches targeting TRIM65 for NSCLC treatment, and also overcoming chemotherapy resistance.
authors.affiliation: Department of Respiration, The First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, The First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Respiration, The First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, The First Hospital of Jilin University, Changchun 130021, China.
authors.forename: Luyao
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Respiration, The First Hospital of Jilin University, Changchun 130021, China. Electronic address: zhenxiangyu2015@gmail.com.
authors.forename: Zhenxiang
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D014162:Transfection; D000070584:Tripartite Motif Proteins; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D000070584:Tripartite Motif Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C000589384:TRIM65 protein, human; D002945:Cisplatin
keywords: NSCLC; TRIM65; Ubiquitination; p53