Epigenetic silencing of miR-296 and miR-512 ensures hTERT dependent apoptosis protection and telomere maintenance in basal-type breast cancer cells
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Roberto Dinami1,2,*, Valentina Buemi1,3,*, Rosanna Sestito2,*,**, Antonina Zappone1,3, Yari Ciani4, Miguel Mano5, Eleonora Petti1,2,3, Andrea Sacconi6, Giovanni Blandino6, Mauro Giacca5, Silvano Piazza4, Roberta Benetti7,8 and Stefan Schoeftner1,2,3
1Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Genomic Stability Unit, Trieste 34149, Italy
2Italian National Cancer Institute, Regina Elena, Rome 00144, Italy
3Department of Life Sciences, Università degli Studi di Trieste, Trieste 34127, Italy
4Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Bioinformatics and Functional Genomics Unit (BFGU), Trieste 34149, Italy
5International Centre for Genetic Engineering and Biotechnology (ICGEB), Molecular Medicine Laboratory, Trieste 34149, Italy
6Italian National Cancer Institute, Regina Elena, Translational Oncogenomics Group, Rome 00144, Italy
7Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Cancer Epigenetics Unit, Trieste 34149, Italy
8Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine 33100, Italy
*These authors have contributed equally to this work
**Current address: Italian National Cancer Institute, Regina Elena, Preclinical Models and New Therapeutic Agents Unit, Via Elio Chianesi 53, Rome 00144, Italy
Roberta Benetti, email: firstname.lastname@example.org
Stefan Schoeftner, email: email@example.com
Keywords: miR-296-5p; miR-512-5p; telomerase; telomeres; breast cancer
Received: August 17, 2016 Accepted: August 27, 2017 Published: September 23, 2017
The catalytic subunit of the telomerase complex, hTERT, ensures unlimited proliferative potential of cancer cells by maintaining telomere function and protecting from apoptosis. Using a miRNA screening approach we identified miR-296-5p and miR-512-5p as miRNAs that target hTERT in breast cancer cells. Ectopic miR-296-5p and miR-512-5p reduce telomerase activity, drive telomere shortening and cause proliferation defects by enhancing senescence and apoptosis in breast cancer cells. In line with the relevance of hTERT expression for human cancer we found that miR-296-5p and miR-512-5p expression is reduced in human breast cancer. Accordingly, high expression of miR-296-5p and miR-512-5p target genes including hTERT is linked with significantly reduced distant metastasis free survival and relapse free survival of basal type breast cancer patients. This suggests relevance of the identified miRNAs in basal type breast cancer. Epigenetic silencing of miR-296 and miR-512 encoding genes is responsible for low levels of miR-296-5p and miR-512-5p expression in basal type breast cancer cells. Disrupting gene silencing results in a dramatic upregulation of miR-296-5p and miR-512-5p levels leading to reduced hTERT expression and increased sensitivity to the induction of apoptosis. Altogether, our data suggest that epigenetic regulatory circuits in basal type breast cancer may contribute to high hTERT levels by silencing miR-296-5p and miR-512-5p expression, thereby contributing to the aggressiveness of basal type breast cancer.
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