Dataset Information

LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-?B activity in nasopharyngeal carcinoma.

ABSTRACT: Long-palate, lung and nasal epithelium clone 1 (LPLUNC1) is a tumour suppressor gene in nasopharyngeal carcinoma (NPC), and low expression of LPLUNC1 is associated with poor prognosis. Our previous study showed that LPLUNC1 upregulates Prohibitin 1 (PHB1), a pleiotropic protein that functions as a tumour suppressor gene in various cancers. Low expression of PHB1 was also found to be associated with the poor prognosis of NPC patients. However, the mechanisms by which LPLUNC1 upregulates PHB1 and the potential role of PHB1 in NPC are unclear. Here, we found that LPLUNC1 stabilised PHB1 by inhibiting PHB1 ubiquitination, which is mediated by E3 ligase TRIM21. LPLUNC1 competitively impaired the binding of PHB1 to TRIM21 due to its stronger binding affinity to PHB1, suppressing the ubiquitination of PHB1. Therefore, our study indicates that PHB1 acted as a tumour suppressor gene by inhibiting NF-?B activity. Depletion of PHB1 significantly attenuated the anti-tumour effects of LPLUNC1 in NPC cells, and the inhibitory effect of LPLUNC1 on NF-?B activity was thus reversed. Together, our findings revealed a novel mechanism underlying the anticancer effect of LPLUNC1 and clarified that PHB1 may represent a novel, promising candidate tumour suppressor gene in NPC, with potential therapeutic target value.

SUBMITTER: Wang H

PROVIDER: S-EPMC6756001 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-κB activity in nasopharyngeal carcinoma.

Wang Heran H Zhou Yujuan Y Oyang Linda L Han Yaqian Y Xia Longzheng L Lin Jingguan J Tang Yanyan Y Su Min M Tan Shiming S Tian Yutong Y Chen Xiaoyan X Luo Xia X Liang Jiaxin J Rao Shan S Wang Ying Y Xiong Wei W Zeng Zhaoyang Z Wang Hui H Li Guiyuan G Liao Qianjin Q

Oncogene 20190318 25

Long-palate, lung and nasal epithelium clone 1 (LPLUNC1) is a tumour suppressor gene in nasopharyngeal carcinoma (NPC), and low expression of LPLUNC1 is associated with poor prognosis. Our previous study showed that LPLUNC1 upregulates Prohibitin 1 (PHB1), a pleiotropic protein that functions as a tumour suppressor gene in various cancers. Low expression of PHB1 was also found to be associated with the poor prognosis of NPC patients. However, the mechanisms by which LPLUNC1 upregulates PHB1 and ...[more]

PMID: 30886235

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Project description:BackgroundCastration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored.MethodsSeveral public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms.ResultsPHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells.ConclusionOur data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC.

Dataset Information

LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-?B activity in nasopharyngeal carcinoma.

Publications

LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-κB activity in nasopharyngeal carcinoma.

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