Hypoxia-inducible PRMT2 addiction in cancers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE235438 | GEO | 2024/04/01
REPOSITORIES: GEO
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Project description:Here we show that PRMT2 is highly expressed in GBM, which is correlated with poor prognosis. The silencing of PRMT2 inhibits GBM cell growth and glioblastoma stem cell self-renewal in vitro and suppreses orthotopic tumor growth. Transcriptome analysis demonstrated that PRMT2 depletion leads to significant deregulation of genes mainly associated with cell cycle progression and pathways in cancer. In agreement with previously published results, we show that PRMT2 is responsible for H3R8 asymmetric methylation (H3R8me2a) and that H3R8me2a enrichment at promoters and enhancers is closely correlated with known active histone marks. Furthermore, we show that PRMT2-mediated H3R8me2a is required for the maintenance of target gene expression and that the catalytic activity of PRMT2 is required for its protumorigenic functions. Taken together, this study demonstrates that PRMT2 acts as a transcriptional co-activator for oncogenic gene expression programs in GBM pathogenesis and provides a rationale for PRMT2 targeting in aggressive gliomas.
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Project description:DNA binding profiling of endogenous HIF1A on proximal promoters in human HeLa cells exposed to 1% oxygen (hypoxia), using normoxic cells (21% oxygen) as reference.<br><br>Biological background: The Hypoxia Inducible Factor Family of transcription factors is proposed as the main orchestrator of the cellular response to hypoxia. HIFs are heterodimers of a HIF alpha and a HIF beta subunit. HIF alpha protein stability is regulated by oxygen-dependent proteasomal degradation, and hence HIFs are strongly stabilized in hypoxia.<br><br>Purpose of the study: a number of HIF1 ChIP-chip studies have been reported, employing various cell types, array platforms and HIF antibodies, and the overlap of HIF binding locations in these studies is relatively small. The aim of this study was to characterize HIF1 binding in an additional cell line (HeLa), and employing a different HIFalpha antibody.<br><br>Experimental design: We conducted a total of six hybridizations employing four biological replicates. For two biological replicates, we performed dye-swap technical replicate experiments.<br><br>Results summary: We identified 55 HIF binding locations in HeLa cells (FDR<2%). While this number is relatively low compared to previous studies, presumably due to limiting antibody sensitivity, the overlap with data from other cell lines is comparable to our HeLa data.
2012-05-20 | E-MEXP-3499 | biostudies-arrayexpress
Project description:Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs) and is involved in various cellular processes, including cancer development. PRMT2 expression is increased in several cancer types although its role in acute myeloid leukemia (AML) remains unknown. Here, we investigate the role of PRMT2 in a cohort of patients with AML, PRMT2 knockout AML cell lines as well as a Prmt2 knockout mouse model. In patients, low PRMT2 expressors are enriched for inflammatory signatures, including the NF-κB pathway, and show inferior survival. In keeping with a role for PRMT2 in control of inflammatory signaling, bone marrow-derived macrophages from Prmt2 KO mice display increased pro-inflammatory cytokine signaling upon LPS treatment. In PRMT2-depleted AML cell lines, aberrant inflammatory signaling has been linked to overproduction of IL6, resulting from a deregulation of the NF-κB signaling pathway, therefore leading to hyperactivation of STAT3. Together, these findings identify PRMT2 as a key regulator of inflammation in AML.
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Project description:Glioblastoma (GBM) is characterized by a high degree of hypoxia. Hypoxia-inducible factors (HIFs) modulate glioma stem-like cell (GSC) responses to hypoxia and promote GBM progression, therapeutic resistance, and recurrence. Here we identify a new transcript of the long non-coding RNA LUCAT1 and show that it reinforces HIF1⍺ signaling in GSCs under hypoxia. LUCAT1 expression is highly induced under hypoxia in GBM and GSCs in a HIF1⍺-dependent manner. High LUCAT1 expression in human GBM correlates with increased aggression and poor survival. Mechanistically, LUCAT1 associates with chromatin and modulates interaction between HIF1⍺ and coactivator CBP to hypoxia response elements (HREs) to drive HIF1⍺-target gene expression under hypoxia. Thus, LUCAT1 acts as a positive feedback factor to augment HIF1⍺ signaling under hypoxic stress in GSCs. Loss of LUCAT1 reduces tumor growth and prolongs mouse survival in xenograft models of GBM. Our findings provide new insights into how GSCs regulate gene expression under hypoxia and identify LUCAT1 as therapeutic target in GBM.
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Project description:Glioblastoma (GBM) is characterized by a high degree of hypoxia. Hypoxia-inducible factors (HIFs) modulate glioma stem-like cell (GSC) responses to hypoxia and promote GBM progression, therapeutic resistance, and recurrence. Here we identify a new transcript of the long non-coding RNA LUCAT1 and show that it reinforces HIF1⍺ signaling in GSCs under hypoxia. LUCAT1 expression is highly induced under hypoxia in GBM and GSCs in a HIF1⍺-dependent manner. High LUCAT1 expression in human GBM correlates with increased aggression and poor survival. Mechanistically, LUCAT1 associates with chromatin and modulates interaction between HIF1⍺ and coactivator CBP to hypoxia response elements (HREs) to drive HIF1⍺-target gene expression under hypoxia. Thus, LUCAT1 acts as a positive feedback factor to augment HIF1⍺ signaling under hypoxic stress in GSCs. Loss of LUCAT1 reduces tumor growth and prolongs mouse survival in xenograft models of GBM. Our findings provide new insights into how GSCs regulate gene expression under hypoxia and identify LUCAT1 as therapeutic target in GBM.
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Project description:BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4-dependent transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interact with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 enrichment at the hyper-acetylated chromatin regions. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 function and highlight targeting PRMT2/4 for better anti-tumor effect of BET inhibitors and DNA damaging agents.
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Project description:The goal of this study is to determine whether PRMT2 plays a causal role in the impairment of atherosclerosis regression in diabetes. We examined the consequence of deleting PRMT2 in myeloid cells during the regression of atherosclerosis in normal and diabetic mice. We found significant impairment of atherosclerosis regression under normoglycemic conditions in mice lacking PRMT2 (Prmt2-/-) in myeloid cells that mimic the decrease in regression of atherosclerosis in WT mice under diabetic conditions. This was associated with increased plaque macrophage retention. PRMT2-deficient plaque CD68+ cells under normoglycemic conditions showed increased expression of genes involved in cytokine signaling and inflammation compared to WT cells by RNA seq. Thus, the loss of PRMT2 is causally linked to impaired atherosclerosis regression.
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Project description:BRD4 functions as an epigenetic reader and plays a crucial role in regulating transcription and genome stability. Dysregulation of BRD4 is frequently observed in various human cancers. However, the molecular details of BRD4 regulation remain largely unknown. Here, we report that PRMT2- and PRMT4-mediated arginine methylation is pivotal for BRD4-dependent transcription, DNA repair, and tumor growth. Specifically, PRMT2/4 interact with and methylates BRD4 at R179, R181, and R183. This arginine methylation selectively controls a transcriptional program by promoting BRD4 enrichment at the hyper-acetylated chromatin regions. Moreover, BRD4 arginine methylation is induced by DNA damage and thereby promotes its binding to chromatin for DNA repair. Deficiency in BRD4 arginine methylation significantly suppresses tumor growth and sensitizes cells to BET inhibitors and DNA damaging agents. Therefore, our findings reveal an arginine methylation-dependent regulatory mechanism of BRD4 function and highlight targeting PRMT2/4 for better anti-tumor effect of BET inhibitors and DNA damaging agents.
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Project description:In response to the dynamic intra-tumor microenvironment, melanoma cells adopt different phenotypic states possessing distinct biological properties associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia, a major microenvironmental cue, is underpinned by expression of hypoxia-inducible transcription factors (HIFs) that reprogram metabolism and promote pro-angiogenic VEGF expression. HIF1 indirectly represses MITF via the transcription factor bHLHE40/DEC1, and MITF can activate HIF1 expression. Although HIF and MITF share a highly related DNA-binding specificity, it is unclear whether they share a subset of target genes. Moreover, the genome-wide impact of hypoxia on melanoma, which genes are direct HIF targets, and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show, that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 h in hypoxia. Surprisingly, under hypoxia MITF is transiently up-regulated by HIF1 and co-regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo-hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma.
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