Highly Selective HDAC6 inhibitor targets glioblastoma promoting HDAC6 degradation via autophagy inhibition and immune modulation

[Speaker] Jia-Rong Liu:1
[Co-author] Chao-Wu Yu:1, Ji-Wang Chern:1
1:School of Pharmacy, National Taiwan University, Taiwan

Glioblastoma is the most fatal type of primary brain tumor and current treatments for glioblastoma are insufficient. It has been found that HDAC6 is overexpressed in glioblastoma and knockdown of HDAC6 by siRNA can inhibit glioma cell proliferation. Herein, we report a novel highly selective HDAC6 inhibitor, J22352, which has PROTAC-like property triggered by both p62 accumulation and ubiquitination, leading to proteolysis of the aberrantly HDAC6 overexpression in glioblastoma. The decrease of HDAC6 expression by J22352 treatment is as a consequence of anti-migration effect, autophagic cancer cell death and significant tumor growth inhibition in glioblastoma. Moreover, treatment of immunocompetent mice with J22352 revealed increased levels of CD8+ T cells and tumor-associated inflammatory cytokines IL-2 and IFN-gama as well as reduced levels of IL-6. Notably, treating by J22352 can also reduce the immunosuppressive activity of PD-L1, leading to a restoration of host anti-tumor activity in immunocompetent mice bearing GL261 murine glioma cells. These results uncover a novel molecular mechanism for regulating PD-L1 protein expression through HDAC6 inhibitors and reveal the potential of J22352 which induces anticancer effects by inhibiting autophagy and eliciting the immune response against glioblastoma.

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