Widespread alternative polyadenylation regulation reprograms the prostate cancer cell transcriptome upon androgen receptor inhibition.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190153 | GEO | 2022/08/12
REPOSITORIES: GEO
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Project description:Alternative polyadenylation (APA) has recently been recognized as a universal mechanism for gene regulation, but it remains unclear how APA is controlled. Here we report that the Arabidopsis thaliana Protein Arginine Methyltransferase 10 (AtPRMT10) regulates global APA with its protein partner HLP1, a conserved hnRNP A/B protein. HLP1 binds preferentially to A-rich and U-rich cis-elements around polyadenylation sites, thereby linking AtPRMT10 to the control of APA through protein-protein interactions. AtPRMT10 mutations cause significant proximal-to-distal poly(A) site shifts largely overlapping with those in hlp1-1 mutants. Proximal polyadenylation is maintained by AtPRMT10-directed methylation and is mediated in part by methylation of HLP1 at specific arginine residues. Our findings demonstrate that arginine methylation of an RNA-binding protein adds a novel layer of regulation to widespread alternative polyadenylation.
2019-01-01 | GSE69904 | GEO
Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens MDV3100 (enzalutamide), durable responses are limited, presumably due to acquired resistance. Recently, JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of ASH2L genome-wide binding in prostate cancer cells after AR stimulation.
2015-03-02 | E-GEOD-60841 | biostudies-arrayexpress
Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Two-color experiment, in duplicates
2014-04-25 | E-GEOD-55063 | biostudies-arrayexpress
Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of AR, BRD2, BRD3, BRD4, ERG, RNA Pol II and H3K27ac in prostate cancer cells with respect to BET inhibitors
2014-04-25 | E-GEOD-55062 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors
2023-07-15 | E-MTAB-12031 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors
2023-07-15 | E-MTAB-12029 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors.
2023-08-07 | E-MTAB-12536 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors
2023-07-20 | E-MTAB-12990 | biostudies-arrayexpress
Project description:To date there are very few tools to reverse the induced dedifferentiation program in CRPC and to improve the response to the androgen deprivation therapy. Here we report that MAT2A is an important oncogenic cofactor of ERG/EZH2 transcriptional reprogramming impacting significantly the androgenic pathway. Using RNA sequencing coupled with ATAC, here we reveal an important link between ERG/MAT2A and EZH2 that impact on AR signaling pathway. This aberrant epigenetic program can be reversed by MAT2A inhibition which establish a near physiologic AR transcriptional program. Targeting MAT2A alone or in combination with EZH2 inhibitors reverse stemness in multiple models including prostatospheres from human PDX and GEM models of aggressive prostate cancer. Targeting MAT2A enhance the sensitivity to the androgenic blockade by Enzalutamide and to EZH2 inhibitors.
2023-07-15 | E-MTAB-12025 | biostudies-arrayexpress
Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.
2023-10-11 | MTBLS8034 | MetaboLights