Histone Mutations and Bone Cancers

Taylor, Earnest L.

doi:10.1007/978-981-15-8104-5_4

Cited by 9 publications

(4 citation statements)

References 47 publications

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“…Oncohistone mutations that occur within N-terminal histone tails typically function through the deregulation of chromatin modification; in cases such as H3K27M or H3K36M histone variants, these mutations directly impact the ability of H3K27 or H3K36 to support methylation. As described above for H3K27M, the impact on histone PTM occurs both in cis and trans ( Yang et al 2016 ); similar results are reported for H3K36M-driven cancers ( Taylor and Westendorf 2021 ). These global changes to chromatin have the potential to deregulate transcriptional competence and subsequent gene expression on a large scale, which presents a new obstacle toward therapeutic development—how does one identify a deregulated transcriptional target(s) that is of consequence to cancer development?…”

Section: Introductionsupporting

confidence: 79%

A Saccharomyces cerevisiae model and screen to define the functional consequences of oncogenic histone missense mutations

Lemon

Kannan

et al. 2022

G3 Genes|Genomes|Genetics

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Somatic missense mutations in histone genes turn these essential proteins into oncohistones, which can drive oncogenesis. Understanding how missense mutations alter histone function is challenging in mammals as mutations occur in a single histone gene. For example, described oncohistone mutations predominantly occur in the histone H3.3 gene, despite the human genome encoding fifteen H3 genes. To understand how oncogenic histone missense mutations alter histone function, we leveraged the budding yeast model, which contains only two H3 genes, to explore the functional consequences of oncohistones H3K36M, H3G34W, H3G34L, H3G34R, and H3G34V. Analysis of cells that express each of these variants as the sole copy of H3 reveals that H3K36 mutants show different drug sensitivities compared to H3G34 mutants. This finding suggests that changes to proximal amino acids in the H3 N-terminal tail alter distinct biological pathways. We exploited the caffeine sensitive growth of H3K36 mutant cells to perform a high copy suppressor screen. This screen identified genes linked to histone function and transcriptional regulation, including Esa1, a histone H4/H2A acetyltransferase; Tos4, a forkhead-associated domain-containing gene expression regulator; Pho92, an N6-methyladenosine RNA binding protein and Sgv1/Bur1, a cyclin-dependent kinase. We show that the Esa1 lysine acetyltransferase activity is critical for suppression of the caffeine sensitive growth of H3K36R mutant cells while the previously characterized binding interactions of Tos4 and Pho92 are not required for suppression. This screen identifies pathways that could be altered by oncohistone mutations and highlights the value of yeast genetics to identify pathways altered by such mutations.

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Section: Introductionsupporting

confidence: 79%

A Saccharomyces cerevisiae model and screen to define the functional consequences of oncogenic histone missense mutations

Lemon

Kannan

et al. 2022

G3 Genes|Genomes|Genetics

View full text Add to dashboard Cite

show abstract

“…Oncohistone mutations that occur within N-terminal histone tails typically function through the deregulation of chromatin modification; in cases such as H3K27M or H3K36M histone variants, these mutations directly impact the ability of H3K27 or H3K36 to support methylation. As described above for H3K27M, the impact on histone post-translational modification occurs both in cis and trans (7); similar results are reported for H3K36M-driven cancers (10). These global changes to chromatin have the potential to deregulate transcriptional competence and subsequent gene expression on a large scale, which presents a new obstacle towards therapeutic development – how does one identify a deregulated transcriptional target(s) that is of consequence to cancer development?…”

Section: Introductionsupporting

confidence: 78%

A Budding Yeast Model and Screen to Define the Functional Consequences of Oncogenic Histone Missense Mutations

Lemon

Kannan

et al. 2021

Preprint

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Somatic missense mutations in histone genes turn these essential proteins into oncohistones, which can drive oncogenesis. Understanding how missense mutations alter histone function is challenging in mammals as the changes occur in a single histone gene. For example, described oncohistone mutations predominantly occur in the histone H3.3 gene, despite the human genome encoding 15 H3 genes. To understand how oncogenic histone missense mutations alter histone function, we leverage the budding yeast model, which encodes only two H3 genes, to explore the functional consequences of oncohistones H3K36M, H3G34W, H3G34L, H3G34R, and H3G34V. An analysis of cells that express each of these variants as the sole copy of H3 reveals that H3K36-mutants show different drug sensitivities compared to H3G34 mutants. This finding suggests that changes to proximal amino acids in the H3 N-terminal tail alter distinct biological pathways. We exploited the caffeine sensitive growth of H3K36 mutant cells to perform a high copy suppressor screen. This screen identified genes linked to histone function and transcriptional regulation, the histone H4/H2A acetyltransferase, Esa1, a forkhead-associated domain-containing gene expression regulator, Tos4, an m6A RNA binding protein, Pho92, and a cyclin-dependent kinase, Sgv1/Bur1. We show that the Esa1 lysine acetyltransferase activity is critical for suppression of the caffeine sensitive growth of H3K36R mutant cells while neither of the characterized binding interactions of Tos4 nor Pho92 are required for suppression. Finally, Sgv1/Bur1-mediated suppression may occur through a dominant negative mechanism. This screen identifies pathways that could be altered by oncohistone mutations and highlights the value of yeast genetics to identify pathways altered by such mutations.

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“…Epigenetic dysregulation is an evolving hallmark of cancer and results from aberrant epigenetic regulators (such as writers, readers, and erasers) that modify histone and nonhistone proteins to balance the transcription of tumor suppressor genes and oncogenes [12,13]. Recently, aberrant, or dysregulated, epigenetic regulators are overwhelmingly discovered by next-generation sequencing studies in OS samples [5,6,[14][15][16][17][18][19]. Targeting dysregulated erasers such as histone deacetylases (HDACs) can reinstate the epigenetic homeostasis from an abnormal epigenetic landscape and, as a result, they are emerging as druggable targets to treat several types of cancers, including osteosarcoma [1,6,11,20].…”

Section: Introductionmentioning

confidence: 99%

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

Torres

VanCleave

Vollmer

et al. 2021

Cancers

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Dysregulation of histone deacetylases (HDACs) is associated with the pathogenesis of human osteosarcoma, which may present an epigenetic vulnerability as well as a therapeutic target. Domatinostat (4SC-202) is a next-generation class I HDAC inhibitor that is currently being used in clinical research for certain cancers, but its impact on human osteosarcoma has yet to be explored. In this study, we report that 4SC-202 inhibits osteosarcoma cell growth in vitro and in vivo. By analyzing cell function in vitro, we show that the anti-tumor effect of 4SC-202 involves the combined induction of cell-cycle arrest at the G2/M phase and apoptotic program, as well as a reduction in cell invasion and migration capabilities. We also found that 4SC-202 has little capacity to promote osteogenic differentiation. Remarkably, 4SC-202 revised the global transcriptome and induced distinct signatures of gene expression in vitro. Moreover, 4SC-202 decreased tumor growth of established human tumor xenografts in immunodeficient mice in vivo. We further reveal key targets regulated by 4SC-202 that contribute to tumor cell growth and survival, and canonical signaling pathways associated with progression and metastasis of osteosarcoma. Our study suggests that 4SC-202 may be exploited as a valuable drug to promote more effective treatment of patients with osteosarcoma and provide molecular insights into the mechanism of action of class I HDAC inhibitors.

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Histone Mutations and Bone Cancers

Cited by 9 publications

References 47 publications

A Saccharomyces cerevisiae model and screen to define the functional consequences of oncogenic histone missense mutations

A Saccharomyces cerevisiae model and screen to define the functional consequences of oncogenic histone missense mutations

A Budding Yeast Model and Screen to Define the Functional Consequences of Oncogenic Histone Missense Mutations

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

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