PVT1 signals an androgen-dependent transcriptional repression program in prostate cancer cells and a set of the repressed genes predicts high-risk tumors

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dc.contributorLaboratório de Expressão Gênica em Eucariotospt_BR
dc.contributor.authorVideira, Alexandrept_BR
dc.contributor.authorBeckedorff, Felipe Cpt_BR
dc.contributor.authorSilva, Lucas F. dapt_BR
dc.contributor.authorVerjovski-Almeida, Sergiopt_BR
dc.identifier.citationVideira A, Beckedorff FC, Silva LF. , Verjovski-Almeida S. PVT1 signals an androgen-dependent transcriptional repression program in prostate cancer cells and a set of the repressed genes predicts high-risk tumors. Cell. Commun. Signal.. 2021 Jan;19:5. doi:10.1186/s12964-020-00691-x.pt_BR
dc.description.abstractBackground: Androgen receptor (AR) and polycomb repressive complex 2 (PRC2) are known to co-occupy the loci of genes that are downregulated by androgen-stimulus. Long intergenic non-coding RNA (lincRNA) PVT1 is an overexpressed oncogene that is associated with AR in LNCaP prostate cancer cells, and with PRC2 in HeLa and many other types of cancer cells. The possible involvement of PVT1 in mediating androgen-induced gene expression downregulation in prostate cancer has not been explored. Methods: LNCaP cell line was used. Native RNA-binding-protein immunoprecipitation with anti-AR or anti-EZH2 was followed by RT-qPCR with primers for PVT1. Knockdown of PVT1 with specifc GapmeRs (or a control with scrambled GapmeR) was followed by diferentially expressed genes (DEGs) determination with Agilent microarrays and with Signifcance Analysis of Microarrays statistical test. DEGs were tested as a tumor risk classifer with a machine learning Random Forest algorithm run with gene expression data from all TCGA-PRAD (prostate adenocarcinoma) tumors as input. ChIP-qPCR was performed for histone marks at the promoter of one DEG. Results: We show that PVT1 knockdown in androgen-stimulated LNCaP cells caused statistically signifcant expression upregulation/downregulation of hundreds of genes. Interestingly, PVT1 knockdown caused upregulation of 160 genes that were repressed by androgen, including a signifcantly enriched set of tumor suppressor genes, and among them FAS, NOV/CCN3, BMF, HRK, IFIT2, AJUBA, DRAIC and TNFRSF21. A 121-gene-set (out of the 160) was able to correctly predict the classifcation of all 293 intermediate- and high-risk TCGA-PRAD tumors, with a mean ROC area under the curve AUC=0.89±0.04, pointing to the relevance of these genes in cancer aggressiveness. Native RIP-qPCR in LNCaP showed that PVT1 was associated with EZH2, a component of PRC2. PVT1 knockdown followed by ChIP-qPCR showed signifcant epigenetic remodeling at the enhancer and promoter regions of tumor suppressor gene NOV, one of the androgen-repressed genes that were upregulated upon PVT1 silencing. Conclusions: Overall, we provide frst evidence that PVT1 was involved in signaling a genome-wide androgendependent transcriptional repressive program of tumor suppressor protein-coding genes in prostate cancer cells. Identifcation of transcriptional inhibition of tumor suppressor genes by PVT1 highlights the pathway to the investiga‑tion of mechanisms that lie behind the oncogenic role of PVT1 in cancer.pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.relation.ispartofCell Communication and Signalingpt_BR
dc.rightsOpen Accesspt_BR
dc.titlePVT1 signals an androgen-dependent transcriptional repression program in prostate cancer cells and a set of the repressed genes predicts high-risk tumorspt_BR
dc.contributor.externalUniversity of Miami Miller School of Medicinept_BR
dc.contributor.externalUniversidade de São Paulo (USP)pt_BR
dc.subject.keywordLincRNA PVT1pt_BR
dc.subject.keywordProstate cancerpt_BR
dc.subject.keywordPVT1 knockdownpt_BR
dc.subject.keywordGenome-wide transcriptional repressionpt_BR
dc.subject.keywordTumor suppressor genespt_BR
dc.relation.ispartofabbreviatedCell. Commun. Signal.pt_BR
dc.identifier.citationabntv. 19, 5, jan. 2021pt_BR
dc.identifier.citationvancouver2021 Jan;19:5pt_BR
dc.contributor.butantanVideira, Alexandre|:Aluno|:Laboratório de Parasitologia|:PrimeiroAutorpt_BR
dc.contributor.butantanVerjovski-Almeida, Sergio|:Pesquisador|:Laboratório de Parasitologia|:Autor de correspondênciapt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2014/03620-2pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2018/23693-5pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2012/12005-4pt_BR
dc.sponsorship.butantanCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)¦¦pt_BR
dc.sponsorship.butantanConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)¦¦pt_BR
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