Membrane-associated HDAC11: A potential new therapeutic targeting compartment in cancer cells

Histone deacetylase 11 (HDAC11), the sole member of class IV histone deacetylases, has emerged as a novel and promising therapeutic target in cancer owing to its unique structural and enzymatic properties. Unlike other HDAC family members, HDAC11 exhibits predominant lysine defatty-acylase activity and has been implicated in tumor progression, immune regulation, and metastasis in a cancer type-dependent manner. However, the subcellular localization-specific targeting proteins for therapy have the advantage of minimized off-target and side effects. The localization of HDAC11 in cancer cells remains poorly understood. In this study, I investigated the localization of endogenous HDAC11 in breast cancer cells using biochemical subcellular fractionation. Consistent with previous reports, HDAC11 was detected in nuclear and cytoplasmic fractions. Unexpectedly, HDAC11 was also consistently detected in membrane-enriched fractions across the cell lines examined. This observation identifies a previously unrecognized membrane-associated pool of endogenous HDAC11 in cancer cells. The presence of HDAC11 within membrane fractions suggests potential non-canonical functions beyond epigenetic regulation. This finding could expand the current understanding of HDAC11 biology and provide a foundation for future studies aimed at defining its membrane-associated interactome, substrates, and therapeutic relevance.