Format

Send to

Choose Destination
Oncotarget. 2017 Sep 23;8(56):95674-95691. doi: 10.18632/oncotarget.21180. eCollection 2017 Nov 10.

Epigenetic silencing of miR-296 and miR-512 ensures hTERT dependent apoptosis protection and telomere maintenance in basal-type breast cancer cells.

Author information

1
Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Genomic Stability Unit, Trieste 34149, Italy.
2
Italian National Cancer Institute, Regina Elena, Rome 00144, Italy.
3
Department of Life Sciences, Università degli Studi di Trieste, Trieste 34127, Italy.
4
Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Bioinformatics and Functional Genomics Unit (BFGU), Trieste 34149, Italy.
5
International Centre for Genetic Engineering and Biotechnology (ICGEB), Molecular Medicine Laboratory, Trieste 34149, Italy.
6
Italian National Cancer Institute, Regina Elena, Translational Oncogenomics Group, Rome 00144, Italy.
7
Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Cancer Epigenetics Unit, Trieste 34149, Italy.
8
Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine 33100, Italy.
#
Contributed equally

Abstract

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.

KEYWORDS:

breast cancer; miR-296-5p; miR-512-5p; telomerase; telomeres

Conflict of interest statement

CONFLICTS OF INTEREST To authors declare not to have potential conflicts of interest.

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center