Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma

Gryder, Berkley E.; Pomella, Silvia; Sayers, Carly M.; Wu, Xiaoli; Song, Young K.; Chiarella, Anna M.; Bagchi, Sukriti; Chou, Hsien-Chao; Sinniah, Ranuka; Walton, Ashley; Wen, Xinyu; Rota, Rossella; Hathaway, Nathaniel A.; Zhao, Keji; Chen, Jiji; Vakoc, Christopher R.; Shern, Jack F.; Stanton, Benjamin Z.; Khan, Javed

doi:10.1038/s41588-019-0534-4

Cited by 123 publications

(185 citation statements)

References 56 publications

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“…As described in Figure 1, HDAC1 was also recruited genome-wide, co-bound with high levels of acetylated H3K9Ac and RNA Pol2 engagement (Cluster II). HDAC inhibition at these genes (Cluster II) caused a reduction in HDAC1 and H3K9Ac, but induced hyperacetylation of H3K27Ac at these gene clusters in agreement with other reports 18 . There also was an accumulation of BRD4 specifically at target promoters in keeping with the canonical role of BRD4 in phosphorylating RNA Pol2 to initiate transcription.…”

Section: Hdac Inhibition At Genes Bound By Hdac Without Associated Sesupporting

confidence: 92%

“…In rhabdomyoma cell lines, most of the HDACs were associated with SEs and HDAC inhibition caused a collapse of SEs, BRD4 spreading, loss of RNA Pol2 and a loss of SE driven transcription 18,25 . Similarly loss of transcription after BRD4 inhibition depended on disrupting SE architecture 17,22 .…”

Section: Hdac Inhibition Causes Enhancer Spreading and Local Loss Ofmentioning

confidence: 99%

“…Transcription is largely controlled by acetylation writers such the histone acetyltransferases (HATs), erasers such as the histone deacetylases (HDACs) and readers such as BRD4 which dictate chromatin accessibility to transcription factors and RNA Pol2 to regulate gene expression 18 . The eraser, histone deacetylase HDAC1 has been widely studied as a transcriptional repressor due to its ability to deacetylate histones, compact chromatin and prevent transcription 19 .…”

Section: Introductionmentioning

confidence: 99%

“…Targeting BRD4 causes SEs to collapse leading to a decrease in oncogenic transcription and potent anti-tumor activity and highlights the dependence of cancer cells on SE driven transcription 17,22 . Paradoxically, in rhabdomyosarcoma cell lines, levels of HDAC1 were bound at SEs 18 and facilitated transcription by driving elongation 24,25 . In parallel, HDACs were shown to regulate BRD4 availability in cell lines as HDAC inhibition trapped BRD4 at hyperacetylated sites, decreasing its availability to induce transcription at non-hyperacetylated promoters.…”

Section: Introductionmentioning

confidence: 99%

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HDAC1 regulates the chromatin landscape to establish transcriptional dependencies in chronic lymphocytic leukemia

Lai

Gasparini

et al. 2020

Preprint

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HDAC1 is a key regulator of gene expression in cancer. We identified a critical role for HDAC1 in establishing the transcriptional dependencies essential for survival in chronic lymphocytic leukemia (CLL) by profiling HDAC1 with BRD4, H3K27Ac superenhancers, H4K9Ac, chromatin accessibility signatures, Pol2 measurements and expression signatures to generate a regulatory chromatin landscape. Superenhancers marked by high levels of acetylation and BRD4 paradoxically also recruited the highest levels of HDAC1. HDAC inhibition poisoned transcription at these loci to selectively disrupt B-cell transcription factors and B-cell receptor signaling. HDAC1 was also recruited genome-wide at promoters without superenhancers to repress expression; HDAC inhibition reverses silencing at these loci, which include key microRNA networks that reciprocally downregulate CLL specific survival and driver genes. Our work provides a compelling rationale for profiling HDAC1 across cancers to characterize its role in driving transcriptional dysregulation that is a hallmark of most cancers and develop epigenetic therapeutic strategies.

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Section: Hdac Inhibition At Genes Bound By Hdac Without Associated Sesupporting

confidence: 92%

Section: Hdac Inhibition Causes Enhancer Spreading and Local Loss Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HDAC1 regulates the chromatin landscape to establish transcriptional dependencies in chronic lymphocytic leukemia

Lai

Gasparini

et al. 2020

Preprint

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“…7,9 The interaction of PAX-FOXO1 fusions with the epigenome has become increasingly appreciated. [9][10][11] PAX3-FOXO1 has been found to require BRD4 at superenhancers, suggesting a novel epigenetic vulnerability in FP-RMS. 10 Further, the fusion protein requires CHD4, which is needed for chromatin remodeling, to activate a subset of its target genes.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Shields

Potlapalli

Cuya-Smith

et al. 2020

Preprint

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Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma that continues to present significant challenges to pediatric oncology. There are two major subtypes of pediatric rhabdomyosarcoma, alveolar and embryonal. Alveolar rhabdomyosarcomas are characterized by the presence of a PAX-FOXO1 fusion protein and termed fusion-positive (FP-RMS); embryonal rhabdomyosarcomas (ERMS) lack these fusions and are termed fusion-negative (FN-RMS). Fusion-positive rhabdomyosarcoma (FP-RMS) harbors PAX-FOXO1 fusion proteinsand has a worse overall outcome compared to FN-RMS, underscoring the critical need to identify novel targets for this disease. While fusion proteins remain challenging therapeutic targets, recent studies have begun to reveal the key intersection of PAX-FOXO1 fusion proteins with the malignant epigenome, suggesting that epigenetic proteins may serve as novel targets in FP-RMS. Here, we investigate the contribution of the epigenetic regulator BMI1 to FP-RMS.We examined RNA-seq tumor datasets and determined that BMI1 is robustly expressed in FP-RMS tumors, patient derived xenografts (PDXs), and cell lines. We depleted BMI1 using RNA interference and find that this leads to a marked decrease in cell growth.Next, we used two BMI1 inhibitors, PTC-209 and PTC-028, and showed that BMI1 inhibition decreases cell cycle progression and increases apoptosis in FP-RMS cell lines. In the in vivo setting, targeting BMI1 leads to decreased tumor growth.Mechanistically, we observe that BMI1 inhibition activates the tumor suppressive Hippo pathway. Collectively, these results identify BMI1 as a novel therapeutic vulnerability in

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Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

et al. 2021

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Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion-positive rhabdomyosarcoma, which expresses either PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3-FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient-derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

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Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma

Cited by 123 publications

References 56 publications

HDAC1 regulates the chromatin landscape to establish transcriptional dependencies in chronic lymphocytic leukemia

HDAC1 regulates the chromatin landscape to establish transcriptional dependencies in chronic lymphocytic leukemia

Epigenetic regulator BMI1 promotes fusion-positive rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

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