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Review
. 2022 Jan;27(1):269-279.
doi: 10.1016/j.drudis.2021.08.004. Epub 2021 Aug 13.

Vorinostat in autophagic cell death: A critical insight into autophagy-mediated, -associated and -dependent cell death for cancer prevention

Srimanta Patra  1 , Prakash P Praharaj  1 , Daniel J Klionsky  2 , Sujit K Bhutia  3
Affiliations
Review

Vorinostat in autophagic cell death: A critical insight into autophagy-mediated, -associated and -dependent cell death for cancer prevention

Srimanta Patra et al. Drug Discov Today. 2022 Jan.

Abstract

Histone deacetylases (HDACs) inhibit the acetylation of crucial autophagy genes, thereby deregulating autophagy and autophagic cell death (ACD) and facilitating cancer cell survival. Vorinostat, a broad-spectrum pan-HDAC inhibitor, inhibits the deacetylation of key autophagic markers and thus interferes with ACD. Vorinostat-regulated ACD can have an autophagy-mediated, -associated or -dependent mechanism depending on the involvement of apoptosis. Molecular insights revealed that hyperactivation of the PIK3C3/VPS34-BECN1 complex increases lysosomal disparity and enhances mitophagy. These changes are followed by reduced mitochondrial biogenesis and by secondary signals that enable superactivated, nonselective or bulk autophagy, leading to ACD. Although the evidence is limited, this review focuses on molecular insights into vorinostat-regulated ACD and describes critical concepts for clinical translation.

Keywords: Autophagy; Cancer; Cell death; Histone deacetylases; Vorinostat.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.. Intricate role of vorinostat-regulated autophagy in cell death.
Vorinostat-regulated autophagic cell death (ACD) can be grouped into autophagy-mediated, -associated and -dependent modes depending on the involvement of apoptosis. In autophagy-mediated death (autophagic facilitation of apoptotic cell death) cell, the autophagy pathway activates the apoptotic cell death pathways. In autophagy-associated cell death (in which autophagic and apoptotic cell death co-exist), the induction of autophagy accompanies apoptotic cell death. Autophagy-dependent (autophagy as an explicit cell death mechanism) cell death occurs independently of the apoptotic and necrotic cell-death pathways.
Figure 2.
Figure 2.. Mechanisms through which vorinostat-regulated autophagy promotes cell death.
Lethal autophagy can be introduced via hyperactivation of the PIK3C3/VPS34–BECN1 complex in the autophagy initiation stage. Apart from direct inhibition of mTOR (MTORC1), vorinostat activates AMP-activated protein kinase (AMPK) and causes the phosphorylation of particular substrates (ULK1, DAPK2), which inhibits mTOR expression. Further modulation of the phosphorylation status of BECN1 by PPP2/PP2A–DAPK1 inhibits its interaction with BCL2 homology domain proteins, leading to the sequestration of BNIP3 and BCLAF1. Despite bypassing canonical initiation of autophagy, the noncanonical pathways drive the formation of autophagosomes. Secondary signals, such as ceramide generation, that recruit mitochondria to the phagophore membranes initiate mitophagy by interacting with LC3-II. Moreover, vorinostat regulates the acetylation of LC3-II to mediate nuclear–cytoplasmic shuttling, which has a substantial role in enhancing autophagosome formation. In addition, vorinostat inhibits the acetylation of HSP90, preventing its nuclear translocation. The inhibition of HSP90 translocation inhibits CDKN2A degradation and facilitates PINK1–PRKN-mediated mitophagy. Furthermore, vorinostat mediates the mitochondrial translocation of NR4A1/Nur77, thereby aiding BNIP3-mediated mitophagy. During the autolysosome maturation stage, vorinostat causes nuclear translocation of Transcription Factor EB (TFEB), leading to further activation of downstream lysosomal targets such as LAMP1, UVRAG, CTSB, CTSD and CTSL and to enhanced lysosomal biogenesis. In addition to lysosomal biogenesis, vorinostat mediates the acetylation of tubulin and KIF1, resulting in enhanced lysosomal transport. During the compromised mitochondrial biogenesis, vorinostat acetylates TP53, which in turn inhibits AMPK and PPARGC1A. Moreover, vorinostat-mediated inhibition of NFE2L2 also inhibits PPARGC1A-mediated mitochondrial biogenesis.
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