HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights

SIMPLE SUMMARY: Autophagy is an essential process in cell recycling, and its involvement in cancer has been increasingly recognized in the last few decades. This mechanism acts as a double-edged sword in tumor progression and is known to either block or promote tumorigenesis in a context-specific manner. Its role in determining chemotherapeutic resistance makes it a potential target in cancer treatment. The two autophagic inhibitors hydroxychloroquine and chloroquine are currently used in the clinic but cause several side effects in tumor patients. Since recent studies also show that epigenetic enzymes such as histone deacetylase (HDAC) proteins are able to modulate autophagy, this review focuses on the ability of HDAC6 to actively regulate the autophagic process. We also explore the possibility of using HDAC6 inhibitors as therapeutic agents in adjuvant treatment or in combination with autophagic modulators to trigger this mechanism, thus avoiding the occurrence and effects of chemoresistance. ABSTRACT: Autophagy is an essential intracellular catabolic mechanism involved in the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism. Its activation enhances cellular tolerance to various stresses and is known to be involved in drug resistance. In cancer, autophagy has a dual role in either promoting or blocking tumorigenesis, and recent studies indicate that epigenetic regulation is involved in its mechanism of action in this context. Specifically, the ubiquitin-binding histone deacetylase (HDAC) enzyme HDAC6 is known to be an important player in modulating autophagy. Epigenetic modulators, such as HDAC inhibitors, mediate this process in different ways and are already undergoing clinical trials. In this review, we describe current knowledge on the role of epigenetic modifications, particularly HDAC-mediated modifications, in controlling autophagy in cancer. We focus on the controversy surrounding their ability to promote or block tumor progression and explore the impact of HDAC6 inhibitors on autophagy modulation in cancer. In light of the fact that targeted drug therapy for cancer patients is attracting ever increasing interest within the research community and in society at large, we discuss the possibility of using HDAC6 inhibitors as adjuvants and/or in combination with conventional treatments to overcome autophagy-related mechanisms of resistance.