miR-128 inhibits telomerase activity by targeting TERT mRNA

Abstract

NOVELTY AND IMPACTTelomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and almost universally provides the molecular basis for unlimited proliferative potential.Expression of human telomerase alone is sufficient for the immortalization of diverse cell types.We have identified the tumor suppressor microRNA (miR-128) as a novel regulator of telomerase, which directly targets the coding sequence (CDS) of TERT mRNA and significantly represses Tert protein expression in a panel of cancer cell lines.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/195198 doi: bioRxiv preprint first posted online Oct. 6, 2017; ABSTRACTTelomerase is a unique cellular reverse transcriptase 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 antimiR 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 Interspaced 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 (RT) by targeting conserved binding sites in the coding region of both enzymes.peer-reviewed)

TERT—Regulation and Roles in Cancer Formation

“…Likewise, miR-1182, miR-1266, miR-532, miR-1207-5p, and miR-3064 suppress gastric, bladder, ovarian cancer growth and invasion by binding to the TERT 3’UTR ( 10 , 79 , 84 , 85 ). Furthermore, miR-128 was found to control TERT expression in HeLa and teratoma cell lines ( 81 , 86 ).…”

Telomeres and telomerase in oncogenesis (Review)

“…Carcinogenic miRNAs may exist as oncogenic miRNAs or suppressor miRNAs that promote or inhibit the development of cancer, respectively. Several miRNAs (miR-128, miR-138, miR-1182, miR-342, miR-491, and miR-541) negatively regulate the expression of the TERT gene, thereby acting as tumor suppressor miRNAs (109). Overexpression of miR-138 has been shown to inhibit cell proliferation, invasion and induce apoptosis in cervical cancer (110).…”

“…Another study found that miR-1182 reduced the proliferation and migration of gastric cancer cells (112). In contrast, miR-128 can act as either oncogenic or suppressor miRNA, depending on interaction with various targets (109). TERC-targeted miRNAs may act as telomerase inhibitors and are being tested in clinical applications.…”

Therapeutic strategies for targeting telomerase in cancer

“…miRNAs are a class of endogenous, noncoding RNAs with regulatory functions that are about 20 to 25 nucleotides in length and play different roles in tumorigenesis: oncogenic miRNAs promote cancer development and tumor suppressor miRNAs . MiRNAs regulate posttranscriptional expressions by complexing with RNA‐induced silencing complexes (RISCs) and base pairing with target mRNAs.…”