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Histone H3K27me3 demethylase act as a regulator of stemness in hypoxic cancer cells that are detached from extracellular matrix

ABSTRACT: Metastasis of cancer cells requires detachment from Extra Cellular Matrix (ECM) to seed cancer cells in a distant organ. Hypoxia is prevalent in this matrix detached cancer cells. Studies have established hypoxia as a chromatin modifier, as it transcriptionally controls expression of various histone demethylases (KDMs); therefore, we hypothesized that the presence of hypoxia could modulate the expression of KDMs in matrix detached cancer cells. Our study showed that in matrix detached cancer cells, both hypoxia and one of the hypoxia regulated H3K27me3 histone demethylase, namely KDM6B, was increased. Simultaneously, we found increased expression of stemness-associated genes, namely SOX-2, SOX-9, and CD44, in hypoxic matrix detached cancer cells. We discovered that KDM6B occupies the promoter region of both SOX-2 and CD44 to regulate their expression epigenetically. Targeting KDM6B reduces its occupancy, thereby expressing the stemness-related genes in matrix detached cancer cells. Further, we noticed increased occupancy of HIF1α promoter by KDM6B, suggesting its regulatory role in maintaining hypoxia in matrix detached cancer cells. This observation was further strengthened as we found a significant positive association between KDM6B and HIF1α in various cancer types. Overall, we found that matrix detachment modulates epigenome by inducing KDM6B activity to regulate the expression of stemness-related genes and hypoxia primarily through HIF1α in matrix detached conditions. KDM6B can be developed as a therapeutic target to eliminate matrix detached cancer cells bound for metastatic events

ORGANISM(S): Homo sapiens

PROVIDER: GSE176558 | GEO | 2021/06/11

REPOSITORIES: GEO

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Hypoxia-mediated regulation of histone demethylases affects angiogenesis associated functions in endothelial cells

Project description:Purpose: Jumonji-containing (jmjC) family of proteins are involved in epigenetic gene regulation through histone specific lysine demethylation. Previous studies have demonstrated that the expression of several members of this family is induced by hypoxia. However, the mechanisms by which lysine specific demethylases (KDMs) are regulated under hypoxia and how they affect angiogenesis, the primary method to restore blood oxygen, remains unknown. In this study, we characterized regulation of KDMs using a combination of nascent and mature mRNA profiling. Furthermore, we aimed to identify KDMs that play a role in mediating the VEGF-mediated angiogenic response in endothelial cells. Results: We demonstrated that majority of KDMs were induced by hypoxia and this effect is more prominent upon constitutive activation of HIF2α compared to HIF1α. Half of the changes in mRNAs levels were attributed to transcriptional regulation as evidenced by similar changes at the level of nascent mRNAs, whereas half was likely due to post-transcriptional mechanisms affecting mature mRNA levels. Hypoxia induced genome-wide redistribution of H3K27me3 at 2000 transcriptionally active loci in human umbilical vein endothelial cells (HUVECs). Among these, we further verified the induction of VEGF-A by demethylation of the locus by KDM4B and KDM6B in response to hypoxia. Accordingly, knockdown of KDM4B and KDM6B led to decreased proliferation and tube formation of HUVECs. Conclusions: Hypoxia leads to both transcriptional and post-transcriptional induction of KDMs and wide redistribution of H3K27me3 at active chromatin regions. Main mediator of angiogenesis, VEGFA, is regulated by KDM4B- and KDM6B- mediated demethylation in HUVECs with functional implications for cell proliferation and tube formation. These findings provide novel insights into the regulation of KDMs by hypoxia and the epigenetic regulation of angiogenesis.

2020-09-03 | GSE139678 | GEO

RNA levels in wild-type and HIF1α-mutant MCF7 cells in normoxia (21% O2), and in hypoxia (1% O2) for 3 h or 24 h

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2024-03-11 | GSE122059 | GEO

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

Project description:Clear cell renal cell carcinoma (ccRCC), the most common type of renal cancer is often associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), leading to stable expression of hypoxia inducible factors, HIF1α and HIF2α. Although HIF1α functions as a tumor suppressor gene, majority of ccRCCs constitutively express HIF1α, stratifying VHL-deficient ccRCCs into groups which express either both HIF1α and HIF2α (H1H2) or HIF2α exclusively (H2). MicroRNA (miRNA) profiling performed in these two ccRCC subtypes to identify novel molecular mechanisms. ccRCCs were classified into H1H2 and H2 subtypes by immunohostochemical staining of H1F1α and H1F2α expression. Five H1H2 tumor samples and eight H2 tumor samples were used for the study. Matched adjacent normal renal tissues were used as respective controls.

2013-09-30 | E-GEOD-47582 | biostudies-arrayexpress

HILPS, a novel long non-coding RNA essential for global oxygen sensing in human

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2023-10-18 | GSE230388 | GEO

Regulation of HIF1α signaling in ER positive breast cancer by the E3 ubiquitin ligase RBCK1

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2022-02-12 | GSE196274 | GEO

Project description:We report the comprehensive genome-wide binding peaks for key factors inovled in oxygen sensing pathways, such as HIF1α, HIF1β and EglN2. In addition, we also report the genome-wide binding peaks for NRF1 in breast cancer cells We conducted HA-EglN2, HIF1α, HIF1β (ARNT) or NRF1 ChIP-Seq in the T47D cell line that overexpresses HA-EglN2 in the presence of hypoxia (1%) and DMOG treatment. T47D parental cells treated with the same condition followed by HA ChIP-seq served as the control to filter non-specific binding.

2014-07-31 | E-GEOD-59935 | biostudies-arrayexpress

Identification of interacting proteins of lncRNA HIF1α-AS1

Project description:LncRNA Hypoxia-inducible factor 1α-antisense 1 (HIF1α-AS1) is located on the antisense strand of the important Hypoxia-inducible factor 1α (HIF1α) gene, but being transcribed in antisense direction along the HIF1α promoter. Here we used the 3’end biotinylated HIF1a-AS1 RNA and a control RNA for RNA Pulldown and searched for interacting proteins in nuclear extracts of human umbilical vein endothelial cells (HUVEC).

2022-09-23 | PXD023512 | Pride

Transcriptomic analysis of the role of the integrin a6b4 in detached cells

Project description:Analysis of gene expression profiles of matrix-detached cells with and without expression of ITGB4, in clustering and non-clustering conditions. The experiment tested the hypothesis that the integrin beta 4 (ITGB4) mediates a significant amount of pro-survival signaling in matrix-detached conditions. Expression of ITGB4 in cancer is correlated with poor patient survival and is impliated in increased metastatic spread. Survival in matrix-deprived conditions is essential to metastasis and targeting signaling downstream of the integrin beta 4 may help curtail metasasis.

2019-04-16 | GSE115059 | GEO

Comparative proteomics of dying and surviving cancer cells improves the identification of drug targets and sheds light on cell life/death decisions

Project description:Chemotherapeutics cause the detachment and death of adherent cancer cells. When studying the proteome changes to determine the protein target and mechanism of action of anticancer drugs, the still-attached cells are normally used, while the detached cells are usually ignored. Here we tested the hypothesis that proteomes of detached cells contain valuable information and therefore separately analyzed the proteomes of detached and attached HCT-116, A375 and RKO cells obtained 48 h after treatment with 5-fluorouracil, methotrexate and paclitaxel. Combined proteome data provided a more accurate identification of drug targets. Six proteins consistently up- or down-regulated in the detached vs attached cells regardless of the drug and cell type were targeted by siRNA. Knocking down USP11, CTTN, ACAA2 and EIF4H had anti-proliferative effects, targeting UHRF1 additionally sensitized the cells to the anticancer drugs, while knocking down RNF-40 increased cell survival against the treatments. Therefore, these proteins are likely to be involved in general cell death and survival decisions. Adding detached cells to the analysis could become a standard practice in expression proteomics of drug-treated cells.

2018-03-28 | PXD007686 | Pride

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Project description:We created a rat renal congestion model and investigated the effect of renal congestion on hemodynamics and molecular mechanisms. The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats to increase upstream IVC pressure and induce congestion in the left kidney only. Left kidney congestion reduced renal blood flow, glomerular filtration rate, and increased renal interstitial hydrostatic pressure. Tubulointerstitial and glomerular injury and medullary thick ascending limb hypoxia were observed only in the congestive kidneys. Molecules related to extracellular matrix expansion, tubular injury, and focal adhesion were upregulated in microarray analysis. Renal decapsulation ameliorated the tubulointerstitial injury. Electron microscopy captured pericyte detachment in the congestive kidneys. Transgelin and platelet-derived growth factor receptors, as indicators of pericyte-myofibroblast transition, were upregulated in the pericytes and the adjacent interstitium. With the compression of the peritubular capillaries and tubules, hypoxia and physical stress induce pericyte detachment, which could result in extracellular matrix expansion and tubular injury in renal congestion.

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