A novel HDAC6 inhibitor Tubastatin A: Controls HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover and reverses Temozolomide-induced ER stress-tolerance in GBM cells. (10th April 2017)

• Record Type: Journal Article
• Authors: Li, Zong-yang; Zhang, Ce; Zhang, Yuan; Chen, Lei; Chen, Bao-dong; Li, Qing-zhong; Zhang, Xie-jun; Li, Wei-ping
• Is Part Of: Cancer letters. Volume 391(2017)
• Page Start: 89
• Page End: 99
• Publication Date: 2017-04-10
• Subjects: Tubastatin A -- ER stress-tolerance -- HDAC6-p97/VCP -- Ubiquitination -- Autophagy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.01.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Temozolomide (TMZ) is the cornerstone of therapy for glioblastoma multiforme (GBM). However, its efficacy is limited due to the development of multidrug resistance (MDR). In this study, we first identified the occurrence of ER stress-tolerance (ERST) in glioma cells and confirmed that ERST was positively correlated with TMZ resistance. We further showed that the seesaw-effect of HDAC6-p97/VCP (increased HDAC6 and decreased p97/VCP) in glioma cells was crucial to ERST-associated TMZ resistance. Moreover, the combination treatment of Tubastatin A (TUB, a selective inhibitor of HDAC6) and TMZ synergistically overcame ERST, reduced cell viability and induced apoptosis in TMZ-resistant glioma cells. TUB and TMZ triggered pro-apoptotic signals of the unfolded protein response (UPR) and ER stress and reversed the ratio between HDAC6 and p97/VCP, which potentially attenuated the activation of heat shock proteins and mediated the reversal of ERST. The combination treatment also triggered the dissociation of Dynein-HDAC6 and attenuation of the Dynein-Dynactin motor complex. In addition, this treatment induced HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover, which was involved in the degradation and clearance of ubiquitinated misfolded proteins. This effect could be partially reversed by HDAC6 KO and/or p97/VCP overexpression. Therefore, we proposed that glioma cells optimized the clearance of ubiquitinated misfolded proteins via the reinforcement of HDAC6-facilitated autophagy and attenuation of the p97/VCP-mediated ubiquitin-proteasome system (UPS). In conclusion, our findings showed that the balance of HDAC6-p97/VCP was crucial to ERST-associated TMZ resistance and that HDAC6 inhibition might be a synergistic target and strategy along with TMZ for the improvement of clinical glioma treatment. Highlights: Seesaw-effects of HDAC6-p97/VCP in glioma specimens and cells were crucial to ERST. Combination treatment of Tubastatin A (TUB) overcame ERST in TMZ-resistant cells. TUB attenuated heat shock protein responds and Dynein-Dynactin motor complex. TUB promoted HDAC6-p97/VCP-controlled ubiquitination-autophagy turnover.