Oncotarget

Research Papers:

miR-128 inhibits telomerase activity by targeting TERT mRNA

Herlinda Guzman, Katie Sanders, Adam Idica, Aurore Bochnakian, Douglas Jury, Iben Daugaard, Dimitrios G Zisoulis and Irene Munk Pedersen _

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Oncotarget. 2018; 9:13244-13253. https://doi.org/10.18632/oncotarget.24284

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Abstract

Herlinda Guzman1,*, Katie Sanders1,*, Adam Idica1, Aurore Bochnakian1, Douglas Jury1, Iben Daugaard1, Dimitrios G Zisoulis1 and Irene Munk Pedersen1

1Department of Molecular Biology and Biochemistry, Francisco J. Ayala School of Biological Sciences, University of California, Irvine 92697–3900, CA, USA

*These authors contributed equally to this work

Correspondence to:

Irene Munk Pedersen, email: imp@uci.edu

Keywords: telomerase; miR-128; miR; TERT; cancer

Received: November 30, 2017     Accepted: January 09, 2018     Published: January 19, 2018

ABSTRACT

Telomerase is a unique cellular reverse transcriptase (RT) essential for maintaining telomere stability and required for the unlimited proliferation of cancer cells. The limiting determinant of telomerase activity is the catalytic component TERT, and TERT expression is closely correlated with telomerase activity and cancer initiation and disease progression. For this reason the regulation of TERT levels in the cell is of great importance. microRNAs (miRs) function as an additional regulatory level in cells, crucial for defining expression boundaries, proper cell fate decisions, cell cycle control, genome integrity, cell death and metastasis. We performed an anti-miR library screen to identity novel miRs, which participate in the control of telomerase. We identified the tumor suppressor miR (miR-128) as a novel endogenous telomerase inhibitor and determined that miR-128 significantly reduces the mRNA and protein levels of Tert in a panel of cancer cell lines. We further evaluated the mechanism by which miR-128 regulates TERT and demonstrated that miR-128 interacts directly with the coding sequence of TERT mRNA in both HeLa cells and teratoma cells. Interestingly, the functional miR-128 binding site in TERT mRNA, is conserved between TERT and the other cellular reverse transcriptase encoded by Long Interspersed Elements-1 (LINE-1 or L1), which can also contribute to the oncogenic phenotype of cancer. This finding supports the novel idea that miRs may function in parallel pathways to inhibit tumorigenesis, by regulating a group of enzymes (such as RT) by targeting conserved binding sites in the coding region of both enzymes.


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