High-selective HDAC6 inhibitor promotes HDAC6 degradation following autophagy modulation and enhanced antitumor immunity in glioblastoma
Journal
Biochemical Pharmacology
Journal Volume
163
Pages
458-471
Date Issued
2019
Author(s)
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. ? 2019 Elsevier Inc.
SDGs
Other Subjects
antineoplastic agent; gamma interferon; histone deacetylase 1; histone deacetylase 11; histone deacetylase 2; histone deacetylase 3; histone deacetylase 6; histone deacetylase 8; histone deacetylase inhibitor; interleukin 17; interleukin 2; interleukin 6; j 22352; unclassified drug; antineoplastic agent; HDAC6 protein, human; histone deacetylase 6; histone deacetylase inhibitor; quinazoline derivative; animal experiment; animal model; antineoplastic activity; Article; autophagy; brain cancer; cancer inhibition; cell death; cell migration; cell proliferation; cell viability; controlled study; glioblastoma; glioma cell; human; human cell; immune response; male; mouse; nonhuman; priority journal; protein degradation; protein expression; tumor immunity; animal; autophagy; cell survival; chemical structure; chemistry; drug effect; experimental neoplasm; gene expression regulation; glioblastoma; metabolism; nude mouse; synthesis; tumor cell line; Animals; Antineoplastic Agents; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Glioblastoma; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Male; Mice; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Quinazolines
Type
journal article