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LINC01638 promotes epithelial-to-mesenchymal transition in endometriosis epithelial cells by upregulating RHOB via HDAC1 suppression

ABSTRACT: Endometriosis is a common disease in women characterized by the growth of endometrial-like lesions at ectopic sites, associated with chronic pelvic pain and infertility. LINC01638 is a long non-coding RNA (lncRNA) that in several cancers has been implicated in the regulation of proliferation and epithelial-to-mesenchymal transition (EMT). Given that these processes are also important in endometriosis, we investigated the role of LINC01638 in this disease. We found that LINC01638 is upregulated in the epithelial layer of endometriosis lesions, and that knockdown of the gene in 12Z epithelial endometriosis cell line led to reduced proliferation, adhesion, migration and invasion. The reduction in proliferation was associated with increased p21 and p27 expression and G1 phase arrest of 12Z cells, showing that LINC01638 acts as an important epigenetic regulator of endometriosis epithelial cells cell cycle progression. Further, transcriptome analysis of LINC01638 control and knockdown cells revealed that a number of transcription factors associated with EMT are downregulated in the knockdown, including FOXC2, SNAI2, TWIST1 and ZEB1, along with the mesenchymal marker VIM. These genetic and phenotypic changes in 12Z knockdown cells were accompanied by a significant reduction in expression of cytoskeleton regulatory gene RHOB and an upregulation of HDAC1 expression. Chromatin immunoprecipitation analysis and HDAC1 inhibitory treatment in LINC01638 control and knockdown cells indicated that LINC01638 regulates RHOB expression via HDAC1 mediated regulation of its promoter acetylation. In vivo, RHOB is upregulated in the epithelial layer of endometriosis lesions compared to control and endometriosis patient eutopic endometrium, supporting a role in the disease. Together these results indicate that LINC01638 is an epigenetic regulator of pathogenesis of endometriosis promoting proliferation and EMT of endometriosis lesions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281916 | GEO | 2025/02/16

REPOSITORIES: GEO

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Project description:Rationale: Endothelial cells (ECs) line the inner surface of continuous capillaries and form a permselective barrier between blood and tissues to limit paracellular fluid and solute flux. The capillary barrier is maintained by intercellular tight junctions (TJs) which are regulated, in part, by differential activity of small GTPases. Tumor necrosis factor (TNF) causes TJ disassembly in a process dependent upon NF-κB-mediated gene expression. Activated (GTP-bound) RhoB has been identified as a downstream effector of TNF-induced leak both through Rho-associated coiled-coil kinase-mediated phosphorylation of RelA, enhancing TNF-induced NF-κB-mediated gene activation, and through sequestration of Rac1 away from the cell junction, preventing barrier restoration. To date, no TNF-induced, RhoB-selective GTP exchange factor (GEF) has been identified in ECs. Objective: Identify a TNF-induced RhoB specific GEF in capillary ECs. Method and Results: human dermal microvascular ECs (HDMECs) were used because they form TJs. Candidate GEFs were identified by whole transcriptome profiling of HDMECs with or without TNF stimulation. Fifty-seven of 73 known GEFs were expressed in HDMECs and 17 were significantly upregulated by TNF. Functional impact of each of the latter group was assessed by measuring the effects of depletion by short interfering RNA knockdown on TNF-induced reduction of trans-endothelial electrical resistance (TEER) of HDMEC monolayers. Depletions of ArhGEF10 or RhoB or double depletion of ArhGEF10/RhoB similarly decreased TNF-mediated reduction of TEER. ArhGEF10 knockdown prevented TNF-induced disruption of TJ proteins assessed by confocal microscopy. TNF-induced increases in the levels of activated RhoB in HDMEC lysates were markedly reduced with only minimal alterations in RhoA or RhoC activation. Finally, immunoisolated ArhGEF10 selectively catalyzed GTP exchange for GDP in RhoB, but not RhoA or RhoC, in vitro. Conclusion: ArhGEF10 is a TNF-induced RhoB-selective GEF for RhoB in cultured human capillary ECs that contributes to TJ disruption.

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LINC01638 promotes epithelial-to-mesenchymal transition in endometriosis epithelial cells by upregulating RHOB via HDAC1 suppression

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