Cancer-associated histone mutation H2BG53D disrupts DNA–histone octamer interaction and promotes oncogenic phenotypes

Wan, Yi Ching Esther; Leung, Tsz Chui Sophia; Ding, Dongbo; Sun, Xulun; Liu, Jiaxian; Zhu, Lina; Kang, Tze Zhen Evangeline; Du, Yang; Zhang, Yuchen; Zhang, Jitian; Qian, Chengyuan; Huen, Msy; Li, Qing; Chow, Maggie Zi Ying; Zheng, Zongli; Han, Junhong; Goel, Ajay; Wang, Xin; Ishibashi, Toyotaka; Chan, Kui Ming

doi:10.1038/s41392-020-0131-0

Cited by 25 publications

(18 citation statements)

References 11 publications

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“…Together with the findings reported earlier by us 4 , we propose a model in which the H2BG53D mutation weakens the interaction between nucleosomal DNA and histone octamer, elevates the expression of cancer associated genes and leads to enhanced oncogenic properties in PDAC (Fig. 1m).…”

Section: Dear Editorsupporting

confidence: 85%

“…Previous studies on histone H3 oncohistones in pediatric brain cancers 1,2 and chondroblastoma 3 , documented the transcriptomic reprogramming through the alterations of histone modifications. We recently reported the identification of a novel cancer associated mutation, the H2BG53to-D in pancreatic ductal adenocarcinoma (PDAC) 4 . We showed that the H2BG53D mutation weakens the interaction between nucleosomal DNA and histone octamer, subsequently enhances transcription in vitro.…”

Section: Dear Editormentioning

confidence: 99%

“…To examine the effect of the H2BG53D mutation on gene expression we conducted RNA-seq using the CRISPR knock-in H2BG53D mutant and isogenic wild-type clones 4 . We identified 280 upregulated and 262 downregulated genes ( Fig.…”

Section: Dear Editormentioning

confidence: 99%

“…To determine the direct effect of the H2BG53D mutation on gene regulation, we mapped the genomic localization of the G53D-H2B in CRISPR knock-in cell lines 4 by FLAG CUT&RUN assays while using H2A CUT&RUN as internal control (Fig. 1e).…”

Section: Dear Editormentioning

confidence: 99%

See 3 more Smart Citations

The H2BG53D oncohistone directly upregulates ANXA3 transcription and enhances cell migration in pancreatic ductal adenocarcinoma

Wan¹,

Liu²,

Zhu³

et al. 2020

Sig Transduct Target Ther

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Section: Dear Editorsupporting

confidence: 85%

Section: Dear Editormentioning

confidence: 99%

Section: Dear Editormentioning

confidence: 99%

Section: Dear Editormentioning

confidence: 99%

See 2 more Smart Citations

The H2BG53D oncohistone directly upregulates ANXA3 transcription and enhances cell migration in pancreatic ductal adenocarcinoma

Wan¹,

Liu²,

Zhu³

et al. 2020

Sig Transduct Target Ther

Self Cite

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“…G53D mutants increase the gap closure ability and transwell migration of cells, associated with an increased ability of RNA polymerase II to pass through the mutated histone. These observations suggest a possible effect of this mutant on chromatin relaxation and in the oncogenic process [ 92 ].…”

Section: Histone H2b Mutationsmentioning

confidence: 99%

The dark side of histones: genomic organization and role of oncohistones in cancer

Amatori

Tavolaro²,

Gambardella

et al. 2021

Clin Epigenet

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Background The oncogenic role of histone mutations is one of the most relevant discovery in cancer epigenetics. Recurrent mutations targeting histone genes have been described in pediatric brain tumors, chondroblastoma, giant cell tumor of bone and other tumor types. The demonstration that mutant histones can be oncogenic and drive the tumorigenesis in pediatric tumors, led to the coining of the term “oncohistones.” The first identified histone mutations were localized at or near residues normally targeted by post-translational modifications (PTMs) in the histone N-terminal tails and suggested a possible interference with histone PTMs regulation and reading. Main body In this review, we describe the peculiar organization of the multiple genes that encode histone proteins, and the latter advances in both the identification and the biological role of histone mutations in cancer. Recent works show that recurrent somatic mutations target both N-terminal tails and globular histone fold domain in diverse tumor types. Oncohistones are often dominant-negative and occur at higher frequencies in tumors affecting children and adolescents. Notably, in many cases the mutations target selectively only some of the genes coding the same histone protein and are frequently associated with specific tumor types or, as documented for histone variant H3.3 in pediatric glioma, with peculiar tumors arising from specific anatomic locations. Conclusion The overview of the most recent advances suggests that the oncogenic potential of histone mutations can be exerted, together with the alteration of histone PTMs, through the destabilization of nucleosome and DNA–nucleosome interactions, as well as through the disruption of higher-order chromatin structure. However, further studies are necessary to fully elucidate the mechanism of action of oncohistones, as well as to evaluate their possible application to cancer classification, prognosis and to the identification of new therapies.

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Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives

Wang,

Liu,

Zhang

et al. 2024

MedComm

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Gastrointestinal tumors, the second leading cause of human mortality, are characterized by their association with inflammation. Currently, progress in the early diagnosis and effective treatment of gastrointestinal tumors is limited. Recent whole‐genome analyses have underscored their profound heterogeneity and extensive genetic and epigenetic reprogramming. Epigenetic reprogramming pertains to dynamic and hereditable alterations in epigenetic patterns, devoid of concurrent modifications in the underlying DNA sequence. Common epigenetic modifications encompass DNA methylation, histone modifications, noncoding RNA, RNA modifications, and chromatin remodeling. These modifications possess the potential to invoke or suppress a multitude of genes associated with cancer, thereby governing the establishment of chromatin configurations characterized by diverse levels of accessibility. This intricate interplay assumes a pivotal and indispensable role in governing the commencement and advancement of gastrointestinal cancer. This article focuses on the impact of epigenetic reprogramming in the initiation and progression of gastric cancer, esophageal cancer, and colorectal cancer, as well as other uncommon gastrointestinal tumors. We elucidate the epigenetic landscape of gastrointestinal tumors, encompassing DNA methylation, histone modifications, chromatin remodeling, and their interrelationships. Besides, this review summarizes the potential diagnostic, therapeutic, and prognostic targets in epigenetic reprogramming, with the aim of assisting clinical treatment strategies.

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Cancer-associated histone mutation H2BG53D disrupts DNA–histone octamer interaction and promotes oncogenic phenotypes

Cited by 25 publications

References 11 publications

The H2BG53D oncohistone directly upregulates ANXA3 transcription and enhances cell migration in pancreatic ductal adenocarcinoma

The H2BG53D oncohistone directly upregulates ANXA3 transcription and enhances cell migration in pancreatic ductal adenocarcinoma

The dark side of histones: genomic organization and role of oncohistones in cancer

Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives

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