HDAC8 Deacetylates HIF-1α and Enhances Its Protein Stability to Promote Tumor Growth and Migration in Melanoma

SIMPLE SUMMARY: Melanoma is the deadliest form of skin cancer, with its incidence increasing significantly over the past few decades. The hypoxic microenvironment of melanoma gives rise to the expression of hypoxia-inducible factor-1 (HIF-1), which mediates various signaling pathways that lead to melanoma progression. In this study, we aim to identify an epigenetic regulator of HIF-1α that could be targeted for therapeutic interventions in melanoma. Here, we demonstrate that histone deacetylase 8 (HDAC8) deacetylates HIF-1α and enhances its stability. Accordingly, the pharmacological inhibition or the genetic ablation of HDAC8 suppresses the transcriptional activity of HIF-1 and demonstrates anti-cancer effects. Therefore, we suggest HDAC8 as a novel regulator of HIF-1α and a therapeutic target for melanoma treatment. ABSTRACT: Melanoma is the most lethal type of skin cancer, and it causes more than 55,000 deaths annually. Although regional melanoma can be surgically removed, once melanoma metastasizes to other regions of the body, the survival rate drops dramatically. The current treatment options are chemotherapy, immunotherapy, and targeted therapy. However, the low response rate and the development of resistance necessitate the search for a novel therapeutic target in melanoma. Hypoxia-inducible factor-1 α (HIF-1α) is overexpressed in melanoma and plays a crucial role in driving malignant transformation in cancer cells. Here, we identified that histone deacetylase 8 (HDAC8) enhances the protein stability of HIF-1α. HDAC8 directly binds to and deacetylates HIF-1α, thereby promoting its protein stability. This, in turn, upregulates the transcriptional activity of HIF-1α and promotes the expressions of its target genes, such as hexokinase 2 (HK2) and glucose transporter 1 (GLUT1). The inhibition of HDAC8 suppresses the proliferation and metastasis of melanoma cells. Furthermore, HDAC8 is correlated with HIF1A expression and poor prognosis in samples from patients with melanoma. These findings uncover a novel epigenetic mechanism that maintains HIF-1α stability and implicates the potential of HDAC8 inhibitors for melanoma therapy.