Histone deacetylase 6 (HDAC6) is a large multidomain protein that deacetylates lysine residues on cytoplasmic proteins, influencing numerous cellular processes. Both the catalytic and noncatalytic functions of HDAC6 have been implicated in cancer development and progression. Over a decade of research on catalytic domain inhibitors has shown that these drugs are well tolerated, exhibit anticancer activity, and can alleviate chemotherapy-induced peripheral neuropathies. However, their effectiveness in treating solid tumours remains uncertain. HDAC6 activity is regulated by protein–protein interactions and post-translational modifications, which may allosterically influence its catalytic domains. As a result, effective inhibition of HDAC6 in cancer using small molecule inhibitors requires a more sophisticated understanding of its role within tumour cells, including whether its expression correlates with deacetylase activity. A comprehensive understanding of cancer-specific HDAC6 expression, functional activity, and activation states will be critical for refining the use of HDAC6 inhibitors in cancer therapy.

Histone Deacetylase 6 (HDAC6) is a large multidomain protein that deacetylates lysine residues on cytoplasmic proteins, influencing a wide range of cellular processes. Both the catalytic and non-catalytic functions of HDAC6 are implicated in cancer development and progression. Over a decade of clinical trials with catalytic domain inhibitors, such as Ricolinostat (ACY1215), has shown that these drugs are well tolerated and can alleviate chemotherapy-induced peripheral neuropathies. However, their effectiveness in treating solid tumors remains uncertain due to the limited number of clinical trials and the small size of patient cohorts, leading to inconclusive results. HDAC6 activity is regulated by protein-protein interactions and post-translational modifications, which may allosterically influence its catalytic domains. Therefore, targeting HDAC6 in cancer therapy with small molecule inhibitors requires a more sophisticated understanding of its role within the tumor microenvironment, including whether its expression correlates with deacetylase activity. A comprehensive evaluation of both its enzymatic and non-enzymatic functions could be crucial in developing more effective strategies for targeting HDAC6 in cancer.