Targeting histone deacetylase 6 mediates a dual anti‐melanoma effect: Enhanced antitumor immunity and impaired cell proliferation

Abstract

The median survival for metastatic melanoma is in the realm of 8–16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.

Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non–Small Cell Lung Cancer

“…HDAC inhibition results in tumor growth arrest in immunocompetent animal models [39–41]. As HDACs are ubiquitously expressed in many tissues, including immune cells, an outstanding issue is whether some of the reported therapeutic benefits of HDAC inhibitors stem from their effects on immune cells.…”

“…In a nutshell, our findings highlight previously unknown immunomodulatory effects of these two classes of drugs in combination and support their therapeutic testing in lung adenocarcinoma. While not the focus of this study, both agents have direct anti-tumor effects [36, 41, 48, 65]. This raises the exciting possibility that ricolinostat and JQ1 could be utilized in combination as “hybrid” therapies that harness not just direct anti-tumor effects, but also indirect effects via peripheral reshaping of immune cell dynamics and function, converging to foster strong anti-cancer benefits.…”

HDAC6 inhibition prevents TNF-α-induced caspase 3 activation in lung endothelial cell and maintains cell-cell junctions

“…HDAC6 inhibition possesses anti-tumor and anti-inflammation effects [13–15]. HDAC6 has many endogenous substrates including chaperones and cytoskeletal proteins [16].…”

Identification of HDAC6‐Selective Inhibitors of Low Cancer Cell Cytotoxicity

“…Such isoform-selective agents should be valuable tools in linking specific HDAC isoforms to tumorigenic activity, especially considering the number of controversial reports on the role of HDAC6-selective inhibitors in cancer. [11] …”