Telomerase Reverse Transcriptase Activates Transcription of MiR500A to Inhibit Hedgehog Signalling and Promote Cell Invasiveness

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2021 Mar 13

PMID 33713376

Citations 4

Authors

Manuel Bernabe-Garcia

Elena Martinez-Balsalobre

Diana Garcia-Moreno

Jesus Garcia-Castillo

Beatriz Revilla-Nuin

Elena Blanco-Alcaina

Victoriano Mulero

Francisca Alcaraz-Perez

Maria L Cayuela

Affiliations

Soon will be listed here.

Abstract

Telomerase reverse transcriptase (TERT) maintains telomere homeostasis, thus ensuring chromosome stability and cell proliferation. In addition, several telomere-independent functions of human TERT have been described. In this study, we report that TERT binds directly to the TCF binding elements located upstream of the oncomiR miR500A, and induces its transcription. This function was independent of the telomerase activity, as shown with experiments using catalytically inactive TERT and inhibitors of TERT and the TERT RNA component. miR500A was in turn found to target three key components of the Hedgehog signalling pathway: Patched 1; Gli family zinc finger 3; and Cullin 3, thereby promoting cell invasion. Our results point to the crucial role of the TERT-miR500A-Hedgehog axis in tumour aggressiveness and highlight the therapeutic potential of targeting noncanonical TERT functions in cancer.

Citing Articles

Hedgehog pathway and cancer: A new area (Review).

Shen D, Xia Y, Fu Y, Cao Q, Chen W, Zhu Y Oncol Rep. 2024; 52(3).

PMID: 38994763 PMC: 11267502. DOI: 10.3892/or.2024.8775.

Genomic, epigenomic, and transcriptomic signatures for telomerase complex components: a pan-cancer analysis.

Wang J, Dai M, Xing X, Wang X, Qin X, Huang T Mol Oncol. 2022; 17(1):150-172.

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Chicken telomerase reverse transcriptase mediates LMH cell pyroptosis by regulating the nuclear factor-kappa B signaling pathway.

Xiang Y, Yu Y, Li Q, Chen J, Li Y, Cao W Poult Sci. 2022; 101(6):101826.

PMID: 35385822 PMC: 9170928. DOI: 10.1016/j.psj.2022.101826.

Telomerase RNA recruits RNA polymerase II to target gene promoters to enhance myelopoiesis.

Garcia-Castillo J, Alcaraz-Perez F, Martinez-Balsalobre E, Garcia-Moreno D, Rossmann M, Fernandez-Lajarin M Proc Natl Acad Sci U S A. 2021; 118(32).

PMID: 34353901 PMC: 8364177. DOI: 10.1073/pnas.2015528118.

References

Yang P, Ni F, Deng R, Qiang G, Zhao H, Yang M . MiR-362-5p promotes the malignancy of chronic myelocytic leukaemia via down-regulation of GADD45α. Mol Cancer. 2015; 14:190. PMC: 4636774. DOI: 10.1186/s12943-015-0465-3. View

Ramalingam P, Palanichamy J, Singh A, Das P, Bhagat M, Kassab M . Biogenesis of intronic miRNAs located in clusters by independent transcription and alternative splicing. RNA. 2013; 20(1):76-87. PMC: 3866646. DOI: 10.1261/rna.041814.113. View

Liu H, Liu Q, Ge Y, Zhao Q, Zheng X, Zhao Y . hTERT promotes cell adhesion and migration independent of telomerase activity. Sci Rep. 2016; 6:22886. PMC: 4789728. DOI: 10.1038/srep22886. View

Megraw M, Sethupathy P, Corda B, Hatzigeorgiou A . miRGen: a database for the study of animal microRNA genomic organization and function. Nucleic Acids Res. 2006; 35(Database issue):D149-55. PMC: 1669779. DOI: 10.1093/nar/gkl904. View

Hahn W, Stewart S, Brooks M, York S, Eaton E, Kurachi A . Inhibition of telomerase limits the growth of human cancer cells. Nat Med. 1999; 5(10):1164-70. DOI: 10.1038/13495. View

Tiwari A, Saraf S, Verma A, Panda P, Jain S . Novel targeting approaches and signaling pathways of colorectal cancer: An insight. World J Gastroenterol. 2018; 24(39):4428-4435. PMC: 6196338. DOI: 10.3748/wjg.v24.i39.4428. View

Ghosh A, Saginc G, Leow S, Khattar E, Shin E, Yan T . Telomerase directly regulates NF-κB-dependent transcription. Nat Cell Biol. 2012; 14(12):1270-81. DOI: 10.1038/ncb2621. View

He B, Xiao Y, Tang B, Wu Y, Hu C, Xie R . hTERT mediates gastric cancer metastasis partially through the indirect targeting of ITGB1 by microRNA-29a. Sci Rep. 2016; 6:21955. PMC: 4763288. DOI: 10.1038/srep21955. View

Fei D, Sanchez-Mejias A, Wang Z, Flaveny C, Long J, Singh S . Hedgehog signaling regulates bladder cancer growth and tumorigenicity. Cancer Res. 2012; 72(17):4449-58. PMC: 3809830. DOI: 10.1158/0008-5472.CAN-11-4123. View

10.

Chakraborty C, Das S . Profiling cell-free and circulating miRNA: a clinical diagnostic tool for different cancers. Tumour Biol. 2016; 37(5):5705-14. DOI: 10.1007/s13277-016-4907-3. View

11.

Mukherjee S, Firpo E, Wang Y, Roberts J . Separation of telomerase functions by reverse genetics. Proc Natl Acad Sci U S A. 2011; 108(50):E1363-71. PMC: 3250197. DOI: 10.1073/pnas.1112414108. View

12.

Krek A, Grun D, Poy M, Wolf R, Rosenberg L, Epstein E . Combinatorial microRNA target predictions. Nat Genet. 2005; 37(5):495-500. DOI: 10.1038/ng1536. View

13.

Fan D, Ren B, Yang X, Liu J, Zhang Z . Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer. J Exp Clin Cancer Res. 2016; 35(1):177. PMC: 5111270. DOI: 10.1186/s13046-016-0432-x. View

14.

Cai B, Chen W, Pan Y, Chen H, Zhang Y, Weng Z . Inhibition of microRNA-500 has anti-cancer effect through its conditional downstream target of TFPI in human prostate cancer. Prostate. 2017; 77(10):1057-1065. DOI: 10.1002/pros.23361. View

15.

Nakashima M, Nandakumar J, Sullivan K, Espinosa J, Cech T . Inhibition of telomerase recruitment and cancer cell death. J Biol Chem. 2013; 288(46):33171-80. PMC: 3829164. DOI: 10.1074/jbc.M113.518175. View

16.

Uhmann A, Ferch U, Bauer R, Tauber S, Arziman Z, Chen C . A model for PTCH1/Ptch1-associated tumors comprising mutational inactivation and gene silencing. Int J Oncol. 2005; 27(6):1567-75. View

17.

Zhang L, Ding Y, Yuan Z, Liu J, Sun J, Lei F . MicroRNA-500 sustains nuclear factor-κB activation and induces gastric cancer cell proliferation and resistance to apoptosis. Oncotarget. 2015; 6(4):2483-95. PMC: 4385865. DOI: 10.18632/oncotarget.2800. View

18.

Liu N, Ding D, Hao W, Yang F, Wu X, Wang M . hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor. Nucleic Acids Res. 2016; 44(18):8693-8703. PMC: 5062966. DOI: 10.1093/nar/gkw549. View

19.

Lee S, Do I, Lee J, Kim K, Jang J, Sohn I . Gastric cancer (GC) patients with hedgehog pathway activation: PTCH1 and GLI2 as independent prognostic factors. Target Oncol. 2013; 8(4):271-80. DOI: 10.1007/s11523-013-0253-1. View

20.

Yamamoto Y, Kosaka N, Tanaka M, Koizumi F, Kanai Y, Mizutani T . MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma. Biomarkers. 2009; 14(7):529-38. DOI: 10.3109/13547500903150771. View