Regulation of HDAC6 catalytic activity in cancer: the role of post-translational modifications and protein–protein interactions

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.