Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

Anastas, Jamie N.; Zee, Barry M.; Kalin, Jay H.; Kim, Mirhee; Guo, Robyn; Alexandrescu, Sanda; Blanco, Mario Andres; Giera, Stefanie; Gillespie, Shawn; Das, Jayanta; Wu, Muzhou; Nocco, Sarah E.; Bonal, Dennis M.; Nguyen, Quang-Dé; Suvà, Mario L.; Bernstein, B; Alani, Rhoda M.; Golub, Todd R.; Cole, Philip A.; Filbin, Mariella G.; Shi, Yang

doi:10.1016/j.ccell.2019.09.005

Cited by 134 publications

(104 citation statements)

References 89 publications

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“…Taken together, these data support a model in which the H3K27M mutation perturbs the epigenetic regulation AFF4 undergoes across neuroglial development and instead may allow the aberrantly-expressed SEC to contribute to DMG stem-like state maintenance. The presence of the H3K27M mutation exaggerates, but is not required for, response to CDK9 pharmacologic inhibition, suggesting this may reflect a lineage or cell state dependency, similar to observations from other epigenetic agents with therapeutic promise in DMG (44,47).…”

Section: The H3k27m Mutation Perturbs Epigenetic Regulation Of Aff4supporting

confidence: 55%

“…Insights stemming from the identification of the oncohistone H3K27M as the unifying driver of these tumors, however, have introduced the potential for therapies targeting the dysregulated epigenetic milieu imparted by these recurrent mutations. Recognition of the aberrancies introduced across the epigenetic regulatory landscape by the H3K27M mutation has led several groups to explore and define epigenetic therapies such as histone demethylase inhibition (50) or histone deacetylase inhibition (20,47,51,52) as promising therapeutic strategies for DMG. Several of these agents are now moving forward in phase I clinical trials (NCT02717455, NCT03632317, NCT03566199) but have yet to demonstrate clinical efficacy.…”

Section: Discussionmentioning

confidence: 99%

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Super elongation complex as a targetable dependency in diffuse midline glioma

Dahl

Danis

Balakrishnan

et al. 2020

Preprint

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AbstractMutations in the histone 3 gene (H3K27M) are the eponymous drivers in diffuse intrinsic pontine gliomas (DIPGs) and other diffuse midline gliomas (DMGs), aggressive pediatric brain cancers for which no curative therapy currently exists. The salient molecular consequence of these recurrent oncohistones is a global loss of repressive H3K27me3 residues and broad epigenetic dysregulation. In order to identify specific, therapeutically targetable epigenetic dependencies within this disease context, we performed an shRNA screen targeting 408 genes classified as epigenetic/chromatin-associated molecules in patient-derived DMG cultures. This approach identified AFF4, the scaffold protein of the super elongation complex (SEC), as a previously-undescribed dependency in DMG. Interrogation of SEC function demonstrated a key role for maintaining DMG cell viability and clonogenic potential while promoting self-renewal of DMG tumor stem cells. Small-molecule inhibition of the SEC with the highly-specific, clinically relevant CDK9 inhibitors atuveciclib and AZD4573 restores regulatory RNA polymerase II pausing, promotes cellular differentiation, and leads to potent anti-tumor effect both in vitro and in patient-derived xenograft models. These studies present a biologic rationale for translational exploration of CDK9 inhibition as a promising therapeutic approach in a disease which currently has no effective medical therapies.

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Section: The H3k27m Mutation Perturbs Epigenetic Regulation Of Aff4supporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Super elongation complex as a targetable dependency in diffuse midline glioma

Dahl

Danis

Balakrishnan

et al. 2020

Preprint

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“…We found that H3.3K27M signi cantly affects the histone PTM landscape, with cell and tissue pro les clustering by mutation status. Further, H3.3K27M is a known dominant-negative inhibitor of H3K27me2/3, and our results corroborate these data, [5,7,8,10,12,13,31]. Of note, a new subgroup of DIPG lacking H3K27M mutation but still exhibiting genomic H3K27me3 loss was recently reported [32]: we did not observe this phenomenon in our cohort (Supplementary material 3).…”

Section: Discussionsupporting

confidence: 92%

Histone Tail Analysis Reveals H3K36me2 And H4K16ac As Epigenetic Signatures of Diffuse Intrinsic Pontine Glioma

An¹,

Camarillo²,

Huang³

et al. 2020

Preprint

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Background: Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles.Methods: We performed targeted mass spectroscopy on H3.3K27M mutant and wild-type tissues (n=12) and cell lines (n=7).Results: We found 29.2% and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in distinct PTMs were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16 amino acid residues. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors relative to wild-type. Further, H3.3K36me2 was the most abundant modification co-occurring on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. BRDi with JQ1 resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro. Conclusion: Taken together, our findings provide insight into the effects of the H3K27M mutation on Histone modification states and response to treatment, and suggest H3K36me2 and H4K16ac in DIPG may represent unique tumor epigenetic signatures for targeted therapy.

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“…The depletion of DUB3 decreases cyclin A levels, leading to cell cycle arrest at the G0/G1-S phase checkpoint in NSCLC cells [23]. Lastly, it is known that histone demethylases can regulate the cell cycle through transcriptional regulation [102]. The histone demethylase PHF8 is stabilized by USP7, leading to the upregulation of cyclin A2, which is critical for cell growth and proliferation in breast carcinomas [36].…”

Section: Dubs and Cell Cycle Controlmentioning

confidence: 99%

Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

Lai

Chen

Tse

2020

IJMS

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Deubiquitinases (DUBs) are involved in various cellular functions. They deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. Studies on the roles of deubiquitylation have been conducted in various cancers to identify the carcinogenic roles of DUBs. In this review, we evaluate the biological roles of DUBs in cancer, including proliferation, cell cycle control, apoptosis, the DNA damage response, tumor suppression, oncogenesis, and metastasis. This review mainly focuses on the regulation of different downstream effectors and pathways via biochemical regulation and posttranslational modifications. We summarize the relationship between DUBs and human cancers and discuss the potential of DUBs as therapeutic targets for cancer treatment. This review also provides basic knowledge of DUBs in the development of cancers and highlights the importance of DUBs in cancer biology.

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Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

Cited by 134 publications

References 89 publications

Super elongation complex as a targetable dependency in diffuse midline glioma

Super elongation complex as a targetable dependency in diffuse midline glioma

Histone Tail Analysis Reveals H3K36me2 And H4K16ac As Epigenetic Signatures of Diffuse Intrinsic Pontine Glioma

Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

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