HDAC6: Tumor Progression and Beyond

Histone Deacetylase 6 (HDAC6) is an intriguing therapeutic target in cancer research, distinguished as the only HDAC family member predominantly located in the cytoplasm. HDAC6 features two catalytic domains and a unique ubiquitin-binding domain, which sets it apart from other HDACs. Beyond its role in histone deacetylation, HDAC6 targets various nonhistone substrates, such as α-tubulin, cortactin, Heat Shock Protein 90 (HSP90), and Heat Shock Factor 1 (HSF1). Its involvement spans critical aspects of tumor progression, including invasion, metastasis, angiogenesis, drug resistance, stemness, and the reduction of tumor cell immunogenicity. Given these functions, HDAC6 inhibitors are emerging as valuable tools in the treatment of both solid and hematological tumors. Recent advancements have seen several HDAC6 inhibitors to enter clinical trials, with promising outcomes reported. This review covers the structural features of HDAC6, its biological roles, and its impact on tumor development, particularly focusing on progression-related events. Additionally, a detailed discussion of preclinical and clinical trials involving selective HDAC6 inhibitors is provided.