High-selective HDAC6 inhibitor promotes HDAC6 degradation following autophagy modulation and enhanced antitumor immunity in glioblastoma

Jia-Rong Liu; Chao-Wu Yu; Pei-Yun Hung; Ling-Wei Hsin; Ji-Wang Chern

doi:10.1016/j.bcp.2019.03.023

High-selective HDAC6 inhibitor promotes HDAC6 degradation following autophagy modulation and enhanced antitumor immunity in glioblastoma

Biochem Pharmacol. 2019 May:163:458-471. doi: 10.1016/j.bcp.2019.03.023. Epub 2019 Mar 15.

Authors

Jia-Rong Liu¹, Chao-Wu Yu², Pei-Yun Hung³, Ling-Wei Hsin¹, Ji-Wang Chern⁴

Affiliations

¹ School of Pharmacy, College of Medicine, National Taiwan University, No. 33, LinSen South Road, Taipei 100, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 100, Taiwan, ROC.
² School of Pharmacy, College of Medicine, National Taiwan University, No. 33, LinSen South Road, Taipei 100, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 100, Taiwan, ROC; AnnJi Pharmaceutical Co., Ltd. No. 18, Siyuan St., Taipei 10087, Taiwan, ROC.
³ AnnJi Pharmaceutical Co., Ltd. No. 18, Siyuan St., Taipei 10087, Taiwan, ROC.
⁴ School of Pharmacy, College of Medicine, National Taiwan University, No. 33, LinSen South Road, Taipei 100, Taiwan, ROC; Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 100, Taiwan, ROC. Electronic address: jwchern@ntu.edu.tw.

PMID: 30885763
DOI: 10.1016/j.bcp.2019.03.023

Abstract

Glioblastoma is the most fatal type of primary brain cancer, and current treatments for glioblastoma are insufficient. HDAC6 is overexpressed in glioblastoma, and siRNA-mediated knockdown of HDAC6 inhibits glioma cell proliferation. Herein, we report a high-selective HDAC6 inhibitor, J22352, which has PROTAC (proteolysis-targeting chimeras)-like property resulted in both p62 accumulation and proteasomal degradation, leading to proteolysis of aberrantly overexpressed HDAC6 in glioblastoma. The consequences of decreased HDAC6 expression in response to J22352 decreased cell migration, increased autophagic cancer cell death and significant tumor growth inhibition. Notably, J22352 reduced the immunosuppressive activity of PD-L1, leading to the restoration of host anti-tumor activity. These results demonstrate that J22352 promotes HDAC6 degradation and induces anticancer effects by inhibiting autophagy and eliciting the antitumor immune response in glioblastoma. Therefore, this highly selective HDAC6 inhibitor can be considered a potential therapeutic for the treatment of glioblastoma and other cancers.

Keywords: Autophagy; Glioblastoma; HDAC6 inhibitor; Immunotherapy; PD-L1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Autophagy
Cell Line, Tumor
Cell Proliferation / drug effects*
Cell Survival
Gene Expression Regulation, Neoplastic / drug effects
Glioblastoma / drug therapy*
Histone Deacetylase 6 / antagonists & inhibitors*
Histone Deacetylase 6 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology
Humans
Male
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy*
Quinazolines / chemical synthesis*
Quinazolines / chemistry
Quinazolines / pharmacology

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Quinazolines
HDAC6 protein, human
Histone Deacetylase 6