The elevated transcription of ADAM19 by the oncohistone H2BE76K contributes to oncogenic properties in breast cancer

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Du Yang
  • Dongbo Ding
  • Saravanan Ramakrishnan
  • Landon Long Chan
  • Siu Yuen Chan
  • Xin Wang
  • Haiyun Gan
  • Junhong Han
  • Toyotaka Ishibashi
  • Qing Li
  • Kui Ming Chan

Detail(s)

Original languageEnglish
Article number100374
Journal / PublicationJournal of Biological Chemistry
Volume296
Online published4 Feb 2021
Publication statusPublished - 2021

Link(s)

Abstract

The recent discovery of the cancer-associated E76K mutation in histone H2B (H2BE76-to-K) in several types of cancers revealed a new class of oncohistone. H2BE76K weakens the stability of histone octamers, alters gene expression, and promotes colony formation. However, the mechanism linking the H2BE76K mutation to cancer development remains largely unknown. In this study, we knock in the H2BE76K mutation in MDA-MB-231 breast cancer cells using CRISPR/Cas9 and show that the E76K mutant histone H2B preferentially localizes to genic regions. Interestingly, genes upregulated in the H2BE76K mutant cells are enriched for the E76K mutant H2B and are involved in cell adhesion and proliferation pathways. We focused on one H2BE76K target gene, ADAM19 (a disintegrin and metalloproteinase-domain-containing protein 19), a gene highly expressed in various human cancers including breast invasive carcinoma, and demonstrate that H2BE76K directly promotes ADAM19 transcription by facilitating efficient transcription along the gene body. ADAM19 depletion reduced the colony formation ability of the H2BE76K mutant cells, whereas wild-type MDA-MB-231 cells overexpressing ADAM19 mimics the colony formation phenotype of the H2BE76K mutant cells. Collectively, our data demonstrate the mechanism by which H2BE76K deregulates the expression of genes that control oncogenic properties through a combined effect of its specific genomic localization and nucleosome destabilization effect.

Research Area(s)

  • oncohistone, breast cancer, ADAM, transcription, epigenetics

Citation Format(s)

The elevated transcription of ADAM19 by the oncohistone H2BE76K contributes to oncogenic properties in breast cancer. / Kang, Tze Zhen Evangeline; Zhu, Lina; Yang, Du; Ding, Dongbo; Zhu, Xiaoxuan; Wan, Yi Ching Esther; Liu, Jiaxian; Ramakrishnan, Saravanan; Chan, Landon Long; Chan, Siu Yuen; Wang, Xin; Gan, Haiyun; Han, Junhong; Ishibashi, Toyotaka; Li, Qing; Chan, Kui Ming.

In: Journal of Biological Chemistry, Vol. 296, 100374, 2021.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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