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.
Highlights
Limitless replicative potential is considered a hallmark of cancer, which is achieved by an inappropriate reactivation of the essential enzyme telomerase [1, 2]
The functional miR-128 binding site in transcriptase protein component (TERT) mRNA, is conserved between TERT and the other cellular reverse transcriptase encoded by Long Interspersed Elements-1 (LINE-1 or L1), which can contribute to the oncogenic phenotype of cancer
This study is the first to identify that miR-128 targets TERT mRNA and reduces TERT mRNA and protein levels resulting in a decrease in telomerase activity in cancer cells
Summary
Limitless replicative potential is considered a hallmark of cancer, which is achieved by an inappropriate reactivation of the essential enzyme telomerase [1, 2]. More than 60% of all protein-coding genes are believed to be subjects of miR regulation and alterations in miR expression can have dire consequences and contribute to the development of a wide variety of human diseases, including cancer [12,13,14,15,16,17]. Depending on their role in carcinogenesis, miRs can generally be divided into oncogenic miRs (oncomiRs) or tumor suppressor miRs that promote or inhibit tumor development and progression, respectively [17,18,19]. MiR-138 has been reported to function as a direct regulator of TERT expression in thyroid carcinoma and at least 5 additional tumor suppressor miRs (let-7g, miR-133a, miR-342, miR-491 and miR-541) have been shown to be capable of regulating TERT expression through direct interaction with TERT mRNA [20, 21]
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