Molecular Determinants of Cancer Therapy Resistance to HDAC Inhibitor-Induced Autophagy

Histone deacetylation inhibitors (HDACi) offer high potential for future cancer therapy as they can re-establish the expression of epigenetically silenced cell death programs. HDACi-induced autophagy offers the possibility to counteract the frequently present apoptosis-resistance as well as stress conditions of cancer cells. Opposed to the function of apoptosis and necrosis however, autophagy activated in cancer cells can engage in a tumor-suppressive or tumor-promoting manner depending on mostly unclarified factors. As a physiological adaption to apoptosis resistance in early phases of tumorigenesis, autophagy seems to resume a tumorsuppressive role that confines tumor necrosis and inflammation or even induces cell death in malignant cells. During later stages of tumor development, chemotherapeutic drug-induced autophagy seems to be reprogrammed by the cancer cell to prevent its elimination and support tumor progression. Consistently, HDACi-mediated activation of autophagy seems to exert a protective function that prevents the induction of apoptotic or necrotic cell death in cancer cells. Thus, resistance to HDACi-induced cell death is often encountered in various types of cancer as well. The current review highlights the different mechanisms of HDACi-elicited autophagy and corresponding possible molecular determinants of therapeutic resistance in cancer.