Expression of the class 1 histone deacetylases HDAC8 and 3 are associated with improved survival of patients with metastatic melanoma

Abstract

Prior studies have shown that combinations of histone deacetylase (HDAC) and BRAF inhibitors (BRAFi) have synergistic effects on BRAFi-resistant melanoma through enhanced apoptosis and inhibition of the cAMPdependent drug resistance pathway. However, little is known about the expression of various HDACs and their associations with BRAF/NRAS mutation status, clinicopathologic characteristics, and patient outcome. The present study extensively profiled HDAC class 1 and their targets/regulators utilizing immunohistochemistry in human melanoma samples from patients with stage IV melanoma, known BRAF/NRAS mutational status, and detailed clinicopatholgical data. HDAC8 was increased in BRAF-mutated melanoma (P = 0.016), however, no association between expression of other HDACs and NRAS/BRAF status was identified. There was also a correlation between HDAC1, HDAC8 expression, and phosphorylated NFκb p65 immunoreactivity (Po0.001). Increased cytoplasmic HDAC8 immunoreactivity was independently associated with an improved survival from both diagnosis of primary melanoma and from first detection of stage IV disease to melanoma death on multivariate analysis (HR 0.992, Po0.001 and HR 0.993,; P = 0.009, respectively). These results suggest not only that HDAC8 may be a prognostic biomarker in melanoma, but also provide important data regarding the regulation of HDACs in melanoma and a rational basis for targeting them therapeutically.

Cooperativity of HOXA5 and STAT3 Is Critical for HDAC8 Inhibition-Mediated Transcriptional Activation of PD-L1 in Human Melanoma Cells

“…Similarly, the analysis of publicly available databases including the Cancer Genome Atlas and the Cancer Cell encyclopedia did not identify any significant relationship between HDAC8 and CD274 mRNA expression. Although HDAC8 is frequently upregulated and the increase is associated with BRAF or NRAS mutation status in melanoma (Wilmott et al, 2015), PD-L1 is subject to regulation by a wide variety of mechanisms (Chen et al, 2016;Kataoka et al, 2016;Pardoll, 2012;Ribas, 2015). It is therefore not surprising that although HDAC8 is involved in regulation of PD-L1 expression, there is no linear relationship between HDAC8 and PD-L1 expression levels.…”

“…These results suggest that exposure to HDAC8 inhibitors may exacerbate immunosuppression in tumor-bearing hosts. Interestingly, high expression of HDAC8 is associated with improved survival of patients with metastatic melanoma (Wilmott et al, 2015). Whether this is related to suppression of PD-L1 thus permitting attack of melanoma cells by T cells remains to be tested.…”

“…In particular, inhibition of the class I HDACs, HDAC1, 2, and 3, upregulates PD-L1 in melanoma cells (Lienlaf et al, 2016;Woods et al, 2015). However, whether the other class I HDAC, HDAC8, is involved in regulating PD-L1 expression remains to be fully defined, whereas the expression of HDAC8 is often upregulated in metastatic melanomas and is associated with improved survival of patients (Wilmott et al, 2015).…”

The inhibition of histone deacetylase 8 suppresses proliferation and inhibits apoptosis in gastric adenocarcinoma

“…Studies have shown that HDAC8 could serve as the prognostic biomarker, promote tumorigenesis and progress in multiple tumors. For example, Wilmott et al (36) found that HDAC8 may be a prognostic biomarker in melanoma, and also provide important data regarding the regulation of HDACs in melanoma and a rational basis for targeting them therapeutically; Wu et al (22) reported that HDAC8 was overexpressed in HCC and HDAC8 knockdown could suppress tumor growth and enhance apoptosis in HCC via elevating the expression of p53 and acetylation of p53 at Lys382, indicating that HDAC8 might serve as a potential therapeutic target in HCC (37); Oehme et al (16) found that the knockdown of HDAC8 resulted in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest and differentiation in cultured neuro blastoma cells; Balasubramanian et al (38) reported that HDAC8-selective inhibitors had a unique mechanism of action involving PLCγ1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies. In the present study, we also found that depletion of HDAC8 using small interference RNA promoted apoptosis and cell cycle arrest in gastric cancer cells, moreover, forced expression of HDAC8 inhibited cell apoptosis and promoted cell proliferation, which suggested that HDAC8 may be a potential therapeutic target of gastric cancer.…”

Histone Modifications, Modifiers and Readers in Melanoma Resistance to Targeted and Immune Therapy

“…Relatively little is known about HDAC expression in melanoma. HDAC8 expression is associated with improved survival in melanoma, but HDAC1 and HDAC8 also correlate with increase phosphorylated p65—a subunit of the NF-κB complex, which is associated with resistance to MAPK inhibitors [ 36 , 37 ].…”