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Review
. 2019 Dec 17;8(12):1656.
doi: 10.3390/cells8121656.

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Paul Peixoto  1   2 , Céline Grandvallet  1 , Jean-Paul Feugeas  1 , Michaël Guittaut  1   3 , Eric Hervouet  1   2   3
Affiliations
Review

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Paul Peixoto et al. Cells. .

Abstract

Although autophagy is a well-known and extensively described cell pathway, numerous studies have been recently interested in studying the importance of its regulation at different molecular levels, including the translational and post-translational levels. Therefore, this review focuses on the links between autophagy and epigenetics in cancer and summarizes the. following: (i) how ATG genes are regulated by epigenetics, including DNA methylation and post-translational histone modifications; (ii) how epidrugs are able to modulate autophagy in cancer and to alter cancer-related phenotypes (proliferation, migration, invasion, tumorigenesis, etc.) and; (iii) how epigenetic enzymes can also regulate autophagy at the protein level. One noteable observation was that researchers most often reported conclusions about the regulation of the autophagy flux, following the use of epidrugs, based only on the analysis of LC3B-II form in treated cells. However, it is now widely accepted that an increase in LC3B-II form could be the consequence of an induction of the autophagy flux, as well as a block in the autophagosome-lysosome fusion. Therefore, in our review, all the published results describing a link between epidrugs and autophagy were systematically reanalyzed to determine whether autophagy flux was indeed increased, or inhibited, following the use of these potentially new interesting treatments targeting the autophagy process. Altogether, these recent data strongly support the idea that the determination of autophagy status could be crucial for future anticancer therapies. Indeed, the use of a combination of epidrugs and autophagy inhibitors could be beneficial for some cancer patients, whereas, in other cases, an increase of autophagy, which is frequently observed following the use of epidrugs, could lead to increased autophagy cell death.

Keywords: DNA methylation; autophagy; cancer; epigenetics; histone deacetylase (HDAC); histone methylation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Interconnection of major autophagy steps. Autophagy induction and initiation of autophagy steps lead both to the cleavage and lipidation of autophagy gene 8 (ATG8) and autophagosome nucleation. ATG8 and protein involved in autophagosome elongation favor the closure of autophagosome and, then, its fusion with lysosome to form an autolysosome and to induce the degradation of its content. AMPK acts as an activator of autophagy, whereas mTOR acts as an inhibitor of autophagy. 3-MA and wortmannin are chemical inhibitors of early steps autophagy, whereas BafA1 blocks the fusion of autophagosomes with lysosomes. Arrows represent a positive action on the target, whereas bar-headed arrows represent an inhibition process.
Figure 2
Figure 2
Model of the balance between autophagy and apoptosis governing cell death. (A) In cancer cells, the combination of an autophagy-mediated pro-survival signal and weak apoptosis led to cancer cell survival. (B) An HDACi can promote a slight increase in apoptosis signaling but also a strong increase in autophagy signaling leading to a balance in favor of autophagy-linked cell death (solid line) or survival (dotted line) depending of both cancer cell model and autophagy induction level. (C) The combination of an HDACi and an autophagy inhibitor (autophagy i) in cells resistant to apoptosis, or in the absence of an external signal of apoptosis, led to a balance in favor of survival via the inhibition of autophagy-linked cell death. (D) The combination of an HDACi and an autophagy inhibitor (autophagy i) led to a balance in favor of apoptosis.
Figure 3
Figure 3
Epigenetic regulation of autophagy in cancer cells. Epigenetic actors and their action on autophagy and cell death are summarized in this figure. A direct transcriptional regulation could be mediated by epigenetic modifiers to promote or inhibit ATG-related genes. An indirect regulation can also be mediated by histones deacetylases and their action on the autophagy process and ROS production. (A) Effects of autophagy inducers/inhibitors or ROS on autophagy-linked cell death or survival; (B) Effects of HDACi and acetylation/deacetylation signaling on autophagy-linked cell death or survival; (C) Effects of histone and DNA methylation regulation and histone ubiquitinylation on autophagy-linked cell death or survival. Inhibitors and miRNA specific of epigenetic modifiers are indicated when their roles have been described in the regulation of autophagy. Arrows represent a positive action on the target whereas bar-headed arrows represent an inhibition. Dotted lines are indicated when the action on the target seems indirect. (clear green: inhibitors; yellow: HDACs; blue: HMTs, pink: HATs; grey: HDMs, purple: other epigenetic proteins).
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