Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics

Ravinder K. Bahia, Xiaoguang Hao, Rozina Hassam, Orsolya Cseh, Danielle A. Bozek, H. Artee Luchman () and Samuel Weiss ()
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Ravinder K. Bahia: University of Calgary
Xiaoguang Hao: University of Calgary
Rozina Hassam: University of Calgary
Orsolya Cseh: University of Calgary
Danielle A. Bozek: University of Calgary
H. Artee Luchman: University of Calgary
Samuel Weiss: University of Calgary

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Histone deacetylases are important epigenetic regulators that have been reported to play essential roles in cancer stem cell functions and are promising therapeutic targets in many cancers including glioblastoma. However, the functionally relevant roles of specific histone deacetylases, in the maintenance of key self-renewal and growth characteristics of brain tumour stem cell (BTSC) sub-populations of glioblastoma, remain to be fully resolved. Here, using pharmacological inhibition and genetic loss and gain of function approaches, we identify HDAC2 as the most relevant histone deacetylase for re-organization of chromatin accessibility resulting in maintenance of BTSC growth and self-renewal properties. Furthermore, its specific interaction with the transforming growth factor-β pathway related proteins, SMAD3 and SKI, is crucial for the maintenance of tumorigenic potential in BTSCs in vitro and in orthotopic xenograft models. Inhibition of HDAC2 activity and disruption of the coordinated mechanisms regulated by the HDAC2-SMAD3-SKI axis are thus promising therapeutic approaches for targeting BTSCs.

Date: 2023
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DOI: 10.1038/s41467-023-40776-y

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