Depletion of JMJD5 sensitizes tumor cells to microtubule-destabilizing agents by altering microtubule stability. Issue 21 (1st November 2016)

• Record Type: Journal Article
• Authors: Wu, Junyu; He, Zhimin; Wang, Da-Liang; Sun, Fang-Lin
• Is Part Of: Cell cycle. Volume 15:Issue 21(2016)
• Page Start: 2980
• Page End: 2991
• Publication Date: 2016-11-01
• Subjects: α-tubulin acetylation -- α-tubulin detyrosination -- colchicine -- drug sensitivity -- JMJD5 -- MAP1B -- microtubule stability -- vinblastine; Cell cycle -- Periodicals; 571.84377
• DOI: 10.1080/15384101.2016.1234548
• Languages: English
• ISSNs: 1538-4101

Abstract

ABSTRACT: Microtubules play essential roles in mitosis, cell migration, and intracellular trafficking. Drugs that target microtubules have demonstrated great clinical success in cancer treatment due to their capacity to impair microtubule dynamics in both mitotic and interphase stages. In a previous report, we demonstrated that JMJD5 associated with mitotic spindle and was required for proper mitosis. However, it remains elusive whether JMJD5 could regulate the stability of cytoskeletal microtubules and whether it affects the efficacy of microtubule-targeting agents. In this study, we find that JMJD5 localizes not only to the nucleus, a fraction of it also localizes to the cytoplasm. JMJD5 depletion decreases the acetylation and detyrosination of α-tubulin, both of which are markers of microtubule stability. In addition, microtubules in JMJD5-depleted cells are more sensitive to nocodazole-induced depolymerization, whereas JMJD5 overexpression increases α-tubulin detyrosination and enhances the resistance of microtubules to nocodazole. Mechanistic studies revealed that JMJD5 regulates MAP1B protein levels and that MAP1B overexpression rescued the microtubule destabilization induced by JMJD5 depletion. Furthermore, JMJD5 depletion significantly promoted apoptosis in cancer cells treated with the microtubule-targeting anti-cancer drugs vinblastine or colchicine. Together, these findings suggest that JMJD5 is required to regulate the stability of cytoskeletal microtubules and that JMJD5 depletion increases the susceptibility of cancer cells to microtubule-destabilizing agents.