Helicase CHD4 is an epigenetic coregulator of PAX3-FOXO1 in alveolar rhabdomyosarcoma

Böhm, Maria; Wachtel, Marco; Marques, Joana G.; Streiff, Natalie; Laubscher, Dominik; Nanni, Paolo; Mamchaoui, Kamel; Santoro, Raffaella; Schäfer, Beat W.

doi:10.1172/jci85057

Cited by 50 publications

(48 citation statements)

References 76 publications

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“…8,9 It has been shown that the ARMSspecific PAX3-FOXO1 fusion oncoprotein interacts with epigenetic modifiers to co-regulate a large proportion of its targets, influencing cellular processes such as differentiation, cell survival, and proliferation. 7 Thus, the fusion oncoproteinpositive ARMS tumors may be more sensitive to epigenetic modification as a therapeutic intervention. Knowing that fusion oncoprotein-positive RMS is less common than fusion oncoprotein-negative tumors, it will be important to consider this difference during clinical trial design, to specifically study this agent for treatment of patients with the ARMS subtype.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Recent studies have shown that, in both ERMS and ARMS, epigenetic dysregulation plays a role in inhibition of terminal myogenic differentiation, and in promotion of proliferative, invasive, and metastatic phenotypes. [4][5][6][7] Genome-wide profiling of DNA methylation in RMS has shown that, while there are common epigenetic aberrations among ERMS and ARMS, they also have distinct epigenetic profiles. [8][9][10] Specifically, fusion-positive (ARMS) tumors showed global decreased methylation when compared to ERMS tumors, with higher frequency of CpG sites that had low methylation, and a lower frequency of CpG that had higher methylation levels.…”

Section: Introductionmentioning

confidence: 99%

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The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma

Ghayad

Rammal

Sarkis

et al. 2018

Cancer Biology & Therapy

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Rhabdomyosarcoma (RMS) is an aggressive childhood sarcoma with two distinct subtypes, embryonal (ERMS) and alveolar (ARMS) histologies. More effective treatment is needed to improve outcomes, beyond conventional cytotoxic chemotherapy. The pan-histone deacetylase inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), has shown promising efficacy in limited preclinical studies. We used a panel of human ERMS and ARMS cell lines and xenografts to evaluate the effects of SAHA as a therapeutic agent in both RMS subtypes. SAHA decreased cell viability by inhibiting S-phase progression in all cell lines tested, and induced apoptosis in all but one cell line. Molecularly, SAHA-treated cells showed activation of a DNA damage response, induction of the cell cycle inhibitors p21 Cip1 and p27 Kip1 and downregulation of Cyclin D1. In a subset of RMS cell lines, SAHA promoted features of cellular senescence and myogenic differentiation. Interestingly, SAHA treatment profoundly decreased protein levels of the driver fusion oncoprotein PAX3-FOXO1 in ARMS cells at a post-translational level. In vivo, SAHA-treated xenografts showed increased histone acetylation and induction of a DNA damage response, along with variable upregulation of p21 Cip1 and p27 Kip1. However, while the ARMS Rh41 xenograft tumor growth was significantly inhibited, there was no significant inhibition of the ERMS tumor xenograft RD. Thus, our work shows that, while SAHA is effective against ERMS and ARMS tumor cells in vitro, it has divergent in vivo effects. Together with the observed effects on the PAX3-FOXO1 fusion protein, these data suggest SAHA as a possible therapeutic agent for clinical testing in patients with fusion protein-positive RMS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma

Ghayad

Rammal

Sarkis

et al. 2018

Cancer Biology & Therapy

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“…Mass spectrometry analysis of the PAX8-containing fractions identified a number of putative PAX8-interacting proteins ( Figure 1D and Table 1). Coincidently, NuRD complex core members, as the helicase CHD4, was also found to be an interactor and epigenetic coregulator of PAX3-FOXO1 in alveolar rhabdomyosarcoma (26).…”

Section: Biochemical Purification Of the Pax8 Complexmentioning

confidence: 96%

PAX8 orchestrates an angiogenic program through interaction with SOX17

Chaves-Moreira

Mitchell

Arruza

et al. 2020

Preprint

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Worldwide, the number of new ovarian cancer cases approaches 300,000 with more than 180,000 deaths every year. The low survival-rate reflects the limitations of current therapies and highlights the importance of identifying new therapeutic targets. Despite significant recent efforts to identify novel vulnerabilities in ovarian cancer, none have led to effective durable therapies with improvement in overall survival. PAX8, a lineage-transcription factor, whose expression is a major molecular feature of ovarian carcinomas, represents a novel therapeutic target. Herein, we have identified SOX17 as a bona fide PAX8-interacting partner and elucidated the impact of this interaction on the development of ovarian cancer. Importantly, we found that PAX8 and SOX17 regulate tumor angiogenesis in vitro and in vivo. The role of PAX8 and SOX17 in the regulation of angiogenesis reveals a novel function for these factors in regulating the tumor microenvironment and highlight this pathway as a viable therapeutic target.

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“…Recent studies have uncovered critical roles for epigenetic mechanisms in the disease-driving effects of PAX3/FOXO1 and the pathogenesis of FP-RMS. This includes activation of enhancers and so-called 'superenhancers (SEs)' by PAX3/FOXO1 itself [7]; utilization of the chromatin factors JARID2, EZH2, CHD4, and BRD4 [7][8][9][10]; and utilization of myogenic transcription factor networks [7]. With the PAX3/FOXO1 oncofusion itself a very difficult therapeutic target, epigenetic mechanisms critically contributing to PAX3/FOXO1 action present exciting alternative targeting opportunities, as recently illustrated for BRD4 [7].…”

Section: Introductionmentioning

confidence: 99%

KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1‐driven and independent disease‐promoting gene expression in fusion‐positive Rhabdomyosarcoma

et al. 2020

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Helicase CHD4 is an epigenetic coregulator of PAX3-FOXO1 in alveolar rhabdomyosarcoma

Cited by 50 publications

References 76 publications

The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma

The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma

PAX8 orchestrates an angiogenic program through interaction with SOX17

KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1‐driven and independent disease‐promoting gene expression in fusion‐positive Rhabdomyosarcoma

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