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Review
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Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53

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Review

Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53

Maria Mrakovcic et al. Int J Mol Sci.

Abstract

Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading to cell cycle arrest, differentiation, and apoptosis. Suberoyl hydroxamic acid (SAHA) is a broad-spectrum histone deacetylase inhibitor (HDACi) suppressing family members in multiple HDAC classes. Increasing evidence indicates that SAHA and other HDACi can, in addition to mitochondria-mediated apoptosis, also promote caspase-independent autophagy. SAHA-induced mTOR inactivation as a major regulator of autophagy activating the remaining autophagic core machinery is by far the most reported pathway in several tumor models. However, the question of which upstream mechanisms regulate SAHA-induced mTOR inactivation that consequently initiate autophagy has been mainly left unexplored. To elucidate this issue, we recently initiated a study clarifying different modes of SAHA-induced cell death in two human uterine sarcoma cell lines which led to the conclusion that the tumor suppressor protein p53 could act as a molecular switch between SAHA-triggered autophagic or apoptotic cell death. In this review, we present current research evidence about HDACi-mediated apoptotic and autophagic pathways, in particular with regard to p53 and its therapeutic implications.

Keywords: Apoptosis; Autophagy; HDAC; HDACi; SAHA; Tumor; p53.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration showing presumed mechanisms mediating SAHA-induced autophagy and its regulation by p53. (A) Acetylated p53 primarily induces apoptosis and nuclear p53 is able to induce basic autophagy by transcriptionally upregulating TSC2, AMPK, and DRAM thereby suppressing mTOR and the ULK1 complex further downstream in MES-SA cells. DRAM upregulation or ATG5 upregulation by the p53-family members, p63 and p73 which can compensate for p53 could besides autophagy also mediate apoptosis; (B) Concurrently, cytoplasmic p53 protein inhibits autophagic cell death by inducing Beclin-1 degradation and/or inhibiting the AMPK-mTOR-ULK1 signaling pathway. It is unclear whether p63 and/or p73 possibly possess transcription-independent regulating functions for autophagy. Dashed line with arrowhead, deacetylating activity of HDAC; Line with arrowhead (HDACi SAHA), activity of SAHA preventing deacetylation; Fork symbols, transcriptional or enzymatic inhibition by indicated proteins; Arrowlines, transcriptional or enzymatic upregulation or activation by indicated proteins, respectively; Double arrow, major pathway activity.
Figure 1
Figure 1
Illustration showing presumed mechanisms mediating SAHA-induced autophagy and its regulation by p53. (A) Acetylated p53 primarily induces apoptosis and nuclear p53 is able to induce basic autophagy by transcriptionally upregulating TSC2, AMPK, and DRAM thereby suppressing mTOR and the ULK1 complex further downstream in MES-SA cells. DRAM upregulation or ATG5 upregulation by the p53-family members, p63 and p73 which can compensate for p53 could besides autophagy also mediate apoptosis; (B) Concurrently, cytoplasmic p53 protein inhibits autophagic cell death by inducing Beclin-1 degradation and/or inhibiting the AMPK-mTOR-ULK1 signaling pathway. It is unclear whether p63 and/or p73 possibly possess transcription-independent regulating functions for autophagy. Dashed line with arrowhead, deacetylating activity of HDAC; Line with arrowhead (HDACi SAHA), activity of SAHA preventing deacetylation; Fork symbols, transcriptional or enzymatic inhibition by indicated proteins; Arrowlines, transcriptional or enzymatic upregulation or activation by indicated proteins, respectively; Double arrow, major pathway activity.
Figure 2
Figure 2
Illustration showing presumed mechanisms mediating SAHA-induced autophagy and its regulation in the absence of p53. (A) Transcription-dependent upregulation of regulatory autophagic or pro-apoptotic gene and protein expression is blocked in the nucleus. p63 and p73 might be able to compensate for p53 in the regulation of autophagy and to a lesser extent in apoptosis; (B) Cytoplasmic p53 protein loss, however, primarily induces autophagy, while apoptosis is disabled. The absence of p53 protein counteracts its suppressive function and could induce autophagic cell death by preventing Beclin-1 degradation and/or reactivating the AMPK-mTOR-ULK1 signaling pathway. Possibly, p63 and/or p73 could contribute to the regulation of autophagy in the cytoplasm. Dashed line with arrowhead, deacetylating activity of HDAC; Line with arrowhead (HDACi SAHA), activity of SAHA preventing deacetylation; Fork symbols, transcriptional or enzymatic inhibition by indicated proteins; Arrowlines, transcriptional or enzymatic upregulation or activation by indicated proteins, respectively; Double arrow, major pathway activity.
Figure 2
Figure 2
Illustration showing presumed mechanisms mediating SAHA-induced autophagy and its regulation in the absence of p53. (A) Transcription-dependent upregulation of regulatory autophagic or pro-apoptotic gene and protein expression is blocked in the nucleus. p63 and p73 might be able to compensate for p53 in the regulation of autophagy and to a lesser extent in apoptosis; (B) Cytoplasmic p53 protein loss, however, primarily induces autophagy, while apoptosis is disabled. The absence of p53 protein counteracts its suppressive function and could induce autophagic cell death by preventing Beclin-1 degradation and/or reactivating the AMPK-mTOR-ULK1 signaling pathway. Possibly, p63 and/or p73 could contribute to the regulation of autophagy in the cytoplasm. Dashed line with arrowhead, deacetylating activity of HDAC; Line with arrowhead (HDACi SAHA), activity of SAHA preventing deacetylation; Fork symbols, transcriptional or enzymatic inhibition by indicated proteins; Arrowlines, transcriptional or enzymatic upregulation or activation by indicated proteins, respectively; Double arrow, major pathway activity.

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