HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights

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.

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…Autophagy promotes the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism [ 103 , 104 ]. HDAC6 is necessary for removal of misfolded proteins [ 105 ] and ubiquitin-mediated protein degradation ( Figure 6 ).…”

“…HDAC6 is necessary for removal of misfolded proteins [ 105 ] and ubiquitin-mediated protein degradation ( Figure 6 ). Among HDACs, HDAC6 is unique in that it has intrinsic ubiquitin-binding activity [ 106 ], which can modulate autophagy [ 103 , 107 , 108 ]. Proteins that are not degraded by proteasomes are sequestered into an insoluble aggresome in HDAC6- and dynein-dependent manners [ 109 ] ( Figure 6 ).…”

Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective

“…It is possible that enzymes such as protein kinases and phosphatases as well as acetylases and ubiquitinates change autophagy-related proteins in response to stressors. The most well-known class IIb deacetylase, histone deacetylase 6 (HDAC6), has been demonstrated to impede autophagy by deacetylating TFEB and FOXO1, two key players in the process [ 23 ]. Additionally, non-coding RNAs including circRNAs, lncRNAs, and microRNAs play a role in autophagy initiation and inhibition [ 24 , 25 ].…”

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

“…Histone deacetylase (HDAC) is a major type of deacetylase that plays important roles in modification of chromosome structures and regulation of gene expression 11,12 . Among the 18 HDACs identified in humans, HDAC6 is unique because it includes a zinc finger domain, two functional deacetylases in tandem, and preferentially localizes in the cytoplasm 13,14 . Accumulating evidence shows that HDAC6 is at the crossroads of infection and innate immunity 15 .…”