Histone acetyltransferase 1 (HAT1) acetylates hypoxia-inducible factor 2 alpha (HIF2A) to execute hypoxia response

Kumar, N and Mondal, M and Arathi, BP and Sundaresan, NR and Somasundaram, K (2023) Histone acetyltransferase 1 (HAT1) acetylates hypoxia-inducible factor 2 alpha (HIF2A) to execute hypoxia response. In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1866 (1).

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Abstract

Hypoxic response to low oxygen levels is characteristic of most solid cancers. Hypoxia-inducible factors (HIFs) regulate cellular metabolism, survival, proliferation, and cancer stem cell growth during hypoxia. The genome-wide analysis identified HAT1, a type B histone acetyltransferase, as an upregulated and essential gene in glioblastoma (GBM). GSEA analysis of differentially regulated genes in HAT1 silenced cells identified significant depletion of “hypoxia” gene sets. Hypoxia conditions induced HIF2A, not HIF1A protein levels in glioma cells in a HAT1-dependent manner. HAT1 and HIF2A interacted with each other and occupied the promoter of VEGFA, a bonafide HIF1A/HIF2A target. Acetylation of K512 and K596 residues by HAT1 is essential for HIF2A stabilization under normoxia and hypoxia as HIF2A carrying acetylation mimic mutations at either of these residues (H512Q or K596Q) showed stable expression in HAT1 silenced cells under normoxia and hypoxia conditions. Finally, we demonstrate that the HAT1-HIF2A axis is essential for hypoxia-promoted cancer stem cell maintenance and reprogramming. Thus, our study identifies that the HAT1-dependent acetylation of HIF2A is vital to executing the hypoxia-induced cell survival and cancer stem cell growth, therefore proposing the HAT1-HIF2A axis as a potential therapeutic target. © 2022 Elsevier B.V.

Item Type:	Journal Article
Publication:	Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Publisher:	Elsevier B.V.
Additional Information:	The copyright for this article belongs to Elsevier B.V.
Keywords:	Acetylation; Glioblastoma; Glioma; GSCs; HAT1; HIF2A; Hypoxia; Oncogene; Reprogramming; Ubiquitination; β-Catenin
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	16 Jan 2023 07:10
Last Modified:	16 Jan 2023 07:10
URI:	https://eprints.iisc.ac.in/id/eprint/79177

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