Downregulation of miR-130b~301b cluster is mediated by aberrant promoter methylation and impairs cellular senescence in prostate cancer.
Numerous DNA-damaging cellular stresses, including oncogene activation and DNA-damage response (DDR), may lead to cellular senescence. Previous observations linked microRNA deregulation with altered senescent patterns, prompting us to investigate whether epigenetic repression of microRNAs expression might disrupt senescence in prostate cancer (PCa) cells.



Differential methylation mapping in prostate tissues was carried using Infinium HumanMethylation450 BeadChip. After validation of methylation and expression analyses in a larger series of prostate tissues, the functional role of the cluster miR-130b~301b was explored using in vitro studies testing cell viability, apoptosis, invasion and DNA damage in prostate cancer cell lines. Western blot and RT-qPCR were performed to support those observations.



We found that the miR-130b~301b cluster directs epigenetic activation of cell cycle inhibitors required for DDR activation, thus stimulating the senescence-associated secretory phenotype (SASP). Furthermore, overexpression of miR-130b~301b cluster markedly reduced the malignant phenotype of PCa cells.



Altogether, these data demonstrate that miR-130b~301b cluster overexpression might effectively induce PCa cell growth arrest through epigenetic regulation of proliferation-blocking genes and activation of cellular senescence.
Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.|Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.|Biomedical Sciences Graduate Program, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal.
João
J
Ramalho-Carvalho
Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.|School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Porto, Portugal.
Inês
I
Graça
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.|Currently at the Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Antonio
A
Gomez
Department of Urology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
Jorge
J
Oliveira
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.|Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal.
Rui
R
Henrique
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain.|Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.
Manel
M
Esteller
Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal. carmenjeronimo@ipoporto.min-saude.pt.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal. carmenjeronimo@ipoporto.min-saude.pt.
Carmen
C
Jerónimo
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D015536:Down-Regulation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics*
C554019:MIRN130 microRNA, human; C550735:MIRN301A microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm
Prostate cancer; Senescence; Senescence-associated secretory phenotype; miR-130b; miR-301b; microRNA