HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation

Qi, Jing; Singh, Sandeep; Hua, Wei; Cai, Qingsong; Chao, Shi Wei; Li, Ling; Liu, Hongjun; Ho, YinWei; Mcdonald, Tinisha; Lin, Allen; Marcucci, Guido; Bhatia, Ravi; Huang, Wei; Chang, Chia-Ling; Kuo, Ya Huei

doi:10.1016/j.stem.2015.08.004

Cited by 88 publications

(98 citation statements)

References 47 publications

(55 reference statements)

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“…A recent study showed that HDAC8 is also responsible for the deacetylation of p53. In inv(16)ϩ leukemia cells, inhibition of p53 deacetylation reactivated p53, and induced apoptosis (28). It is possible that the cell cycle delay and growth arrest we observed in MCF7 cells is also mediated by altered p53 acetylation rather than solely from accumulated ac-SMC3.…”

Section: Hdac8 Inhibition Does Not Mimic Cohesin Depletion In Mcf7mentioning

confidence: 85%

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HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

Dasgupta

Antony

Braithwaite

et al. 2016

Journal of Biological Chemistry

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Cohesin, a multi-subunit protein complex involved in chromosome organization, is frequently mutated or aberrantly expressed in cancer. Multiple functions of cohesin, including cell division and gene expression, highlight its potential as a novel therapeutic target. The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes. Following anaphase, ac-SMC3 is deacetylated by HDAC8. Reversal of SMC3 acetylation is imperative for recycling cohesin so that it can be reloaded in interphase for both non-mitotic and mitotic functions. We blocked deacetylation of ac-SMC3 using an HDAC8-specific inhibitor PCI-34051 in MCF7 breast cancer cells, and examined the effects on transcription of cohesin-dependent genes that respond to estrogen. HDAC8 inhibition led to accumulation of ac-SMC3 as expected, but surprisingly, had no influence on the transcription of estrogen-responsive genes that are altered by siRNA targeting of RAD21 or SMC3. Knockdown of RAD21 altered estrogen receptor ␣ (ER) recruitment at SOX4 and IL20, and affected transcription of these genes, while HDAC8 inhibition did not. Rather, inhibition of HDAC8 delayed cell cycle progression, suppressed proliferation and induced apoptosis in a concentration-dependent manner. We conclude that HDAC8 inhibition does not change the estrogen-specific transcriptional role of cohesin in MCF7 cells, but instead, compromises cell cycle progression and cell survival. Our results argue that candidate inhibitors of cohesin function may differ in their effects depending on the cellular genotype and should be thoroughly tested for predicted effects on cohesin's mechanistic roles.The cohesin complex is a chromatin-associated multi-subunit protein comprised of two SMC (structural maintenance of chromosomes, SMC1A and SMC3) 2 and two non-SMC subunits (RAD21, STAG1/2). Cohesin's canonical function establishes cohesion between replicated sister chromatids, thus ensuring their precise segregation at anaphase (1, 2). Research over the last one and a half decades has revealed that cohesin has additional cohesion-independent functions in interphase nuclei, such as chromatin organization and transcription regulation (3, 4).Recently, cancer genome sequencing projects have revealed that genes encoding cohesin subunits are frequently mutated in several different types of cancer, with particularly high frequency in acute myeloid leukemia (AML) (5-9). Recent mouse models indicate that cohesin contributes to leukemia progression likely through controlling transcription and genome organization, rather than through chromosome separation (10 -12). In breast cancer, the cohesin subunit RAD21 is overexpressed and confers poor prognosis (13,14). We previously showed that cohesin mediates transcription of the MYC gene (15-17) and modulates the transcription of estrogen-dependent genes in MCF7 breast cancer cells (18). The emergence of cohesin as an important contributor to cancer has generated interest in the development of therapeutics that compromise ...

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Section: Hdac8 Inhibition Does Not Mimic Cohesin Depletion In Mcf7mentioning

confidence: 85%

“…In addition to ac-SMC3, acetylated p53 is a target of HDAC8. In inv(16)ϩ AML, chemical inhibition of HDAC8 prevented p53 deacetylation, leading to restoration of p53-induced apoptosis of leukemia-initiating cells (28).…”

mentioning

confidence: 99%

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

Dasgupta

Antony

Braithwaite

et al. 2016

Journal of Biological Chemistry

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“…LSCs rely on oncogenic signals that inactivate the p53 pathway, and reactivation of dormant p53 in LICs can be a selective strategy to eradicate LICs (80–83). Our data suggest that targeting of MDMX with a dual MDMX/MDM2 inhibitor is a strategy to target LICs in AML.…”

Section: Discussionmentioning

confidence: 99%

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

et al. 2018

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The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these inter-actions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled a-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell-enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

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“…77 p53 deacetylation is also triggered by the CBFb-SMMHC FP of inv (16)/t(16;16) AML, which complexes with HDAC8 and p53, thus promoting p53 deacetylation. 78 Additionally, the CBFb-SMMHC/ Runx1 oligomers mislocalize HIPK2 (p53 activator) into cytoplasmic filamentous structures, hence interfering with p53 apoptotic function. 79 The favorable prognosis of this AML and of APL might be explained in part by the presence of a relatively higher TAp73/DNp73 ratio, compensating for wtp53 dysfunction.…”

Section: Aml With Chromosomal Translocationsmentioning

confidence: 99%

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Prokocimer

Molchadsky

Rotter

2017

Blood

138

119

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The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

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HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation

Cited by 88 publications

References 47 publications

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

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