Deciphering the role of histone modifications in uterine leiomyoma: acetylation of H3K27 regulates the expression of genes involved in proliferation, cell signaling, cell transport, angiogenesis and extracellular matrix formation
Author(s)
Carbajo-Garcia, Maria Cristina
de Miguel-Gomez, Lucia
Juarez-Barber, Elena
Trelis, Alexandra
Monleon, Javier
Type
Journal Article
Abstract
Uterine leiomyoma (UL) is a benign tumor arising from myometrium (MM) with a high prevalence and unclear pathology. Histone modifications are altered in tumors, particularly via histone acetylation which is correlated with gene activation. To identify if the acetylation of H3K27 is involved in UL pathogenesis and if its reversion may be a therapeutic option, we performed a prospective study integrating RNA-seq (n = 48) and CHIP-seq for H3K27ac (n = 19) in UL vs MM tissue, together with qRT-PCR of SAHA-treated UL cells (n = 10). CHIP-seq showed lower levels of H3K27ac in UL versus MM (p-value < 2.2 × 10−16). From 922 DEGs found in UL vs. MM (FDR < 0.01), 482 presented H3K27ac. A differential acetylation (FDR < 0.05) was discovered in 82 of these genes (29 hyperacetylated/upregulated, 53 hypoacetylated/downregulated). Hyperacetylation/upregulation of oncogenes (NDP,HOXA13,COL24A1,IGFL3) and hypoacetylation/downregulation of tumor suppressor genes (CD40,GIMAP8,IL15,GPX3,DPT) altered the immune system, the metabolism, TGFβ3 and the Wnt/β-catenin pathway. Functional enrichment analysis revealed deregulation of proliferation, cell signaling, transport, angiogenesis and extracellular matrix. Inhibition of histone deacetylases by SAHA increased expression of hypoacetylated/downregulated genes in UL cells (p < 0.05). Conclusively, H3K27ac regulates genes involved in UL onset and maintenance. Histone deacetylation reversion upregulates the expression of tumor suppressor genes in UL cells, suggesting targeting histone modifications as a therapeutic approach for UL.
Date Issued
2022-06-01
Date Acceptance
2022-05-27
Citation
Biomedicines, 2022, 10 (6), pp.1-14
ISSN
2227-9059
Publisher
MDPI
Start Page
1
End Page
14
Journal / Book Title
Biomedicines
Volume
10
Issue
6
Copyright Statement
© 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Ovarian Cancer Action
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000817632800001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
n/a
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Medicine, Research & Experimental
Pharmacology & Pharmacy
Research & Experimental Medicine
histone modification
gene expression
angiogenesis
extracellular matrix
uterine leiomyoma
POOR-PROGNOSIS
CANCER
OVEREXPRESSION
PATHOGENESIS
SUPPRESSES
ACTIVATION
DIAGNOSIS
PATHWAYS
INVASION
SUBTYPES
Publication Status
Published
Article Number
ARTN 1279
Date Publish Online
2022-05-30