Epigenetic Disruption of miR-130a Promotes Prostate Cancer By Targeting SEC23B and DEPDC1

Authors and Affiliations:

João Ramalho-Carvalho^a,b, João Barbosa Martins^a, Lina Cekaite^c,d, Anita Sveen^c,d, Jorge Torres-Ferreira^a, Inês Graça^a,e, Pedro Costa-Pinheiro^a, Ina Andrassy Eilertsen^c, Luís Antunes^f, Jorge Oliveira^g, Ragnhild A. Lothe^c,d, Rui Henrique^a,h,i, Carmen Jerónimo^a,i*

^aCancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal;

^bBiomedical Sciences Graduate Program, Institute of Biomedical Sciences Abel Salazar– University of Porto (ICBAS-UP), Porto, Portugal;

^cDepartment of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway;

^dCentre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway;

^eSchool of Allied Health Sciences (ESTSP), Polytechnic of Porto, Portugal; Departments of ^fEpidemiology, ^gUrology and ^hPathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal;

ⁱDepartment of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal.

* Corresponding author

Abstract:

MicroRNAs (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing, fine tuning gene expression.

In an initial screen, miRNAs were found to be globally down-regulated in prostate cancer (PCa) cell lines and primary tumours. Exposure of PCa cell lines to a demethylating agent, 5-Aza-CdR resulted in an increase in the expression levels of miRNAs in general. Using stringent filtering criteria miR-130a was identified as the most promising candidate and selected for validation analyses in our patient series. Down-regulation of miR-130a was associated with promoter hypermethylation. MiR-130a methylation levels discriminated PCa from non-malignant tissues (AUC = 0.956), and urine samples revealed high specificity for non-invasive detection of patients with PCa (AUC = 0.89). Additionally, repressive histone marks were also found in the promoter of miR-130a.

Over-expression of miR-130a in PCa cells reduced cell viability and invasion capability, and increased apoptosis. Putative targets of miR-130a were assessed by microarray expression profiling and DEPD1C and SEC23B were selected for validation. Silencing of both genes resembled the effect of over-expressing miR-130a in PCa cells.

Our data indicate that miR-130a is an epigenetically regulated miRNA involved in regulation of key molecular and phenotypic features of prostate carcinogenesis, acting as a tumour suppressor miRNA.

Journal: Cancer Letters

Link: http://www.cancerletters.info/article/S0304-3835(16)30649-8/fulltext?rss=yes