期刊
BIOMEDICINES
卷 10, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/biomedicines10061279
关键词
histone modification; gene expression; angiogenesis; extracellular matrix; uterine leiomyoma
资金
- Instituto de Salud Carlos III [PI18/00323, FI19/00110, CP20/00120]
- Miguel Servet Program Fondo Social Europeo El FSE invierte en tu futuro
- Generalitat Valenciana through VALi+d Programe [ACIF/2019/139, APOTIP/2021/042]
- Generalitat Valenciana/European social fund [BEFPI/2021/013]
- Cancer Research UK Imperial Centre
- National Institute for Health Research Imperial Biomedical Research Centre
- Ovarian Cancer Action Research Centre
H3K27ac is involved in the pathogenesis and maintenance of uterine leiomyoma (UL), and reversal of histone deacetylation upregulates the expression of tumor suppressor genes, suggesting it as a therapeutic approach for UL.
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 x 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, TGF beta 3 and the Wnt/beta-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.
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