title: Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity.
abstract: Constitutively active MYC and reactivated telomerase often coexist in cancers. While reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with cofactors, confers several growth advantages to cancer cells. It is known that the reactivation of TERT, the catalytic subunit of telomerase, is limiting for reconstituting telomerase activity in tumors. However, while reactivation of TERT has been functionally linked to the acquisition of several "hallmarks of cancer" in tumors, the molecular mechanisms by which this occurs and whether these mechanisms are distinct from the role of telomerase on telomeres is not clear. Here, we demonstrated that first-generation TERT-null mice, unlike Terc-null mice, show delayed onset of MYC-induced lymphomagenesis. We further determined that TERT is a regulator of MYC stability in cancer. TERT stabilized MYC levels on chromatin, contributing to either activation or repression of its target genes. TERT regulated MYC ubiquitination and proteasomal degradation, and this effect of TERT was independent of its reverse transcriptase activity and role in telomere elongation. Based on these data, we conclude that reactivation of TERT, a direct transcriptional MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Koh
authors.forename: Ekta
authors.initials: E
authors.lastname: Khattar
authors.forename: Shi Chi
authors.initials: SC
authors.lastname: Leow
authors.forename: Chia Yi
authors.initials: CY
authors.lastname: Liu
authors.forename: Julius
authors.initials: J
authors.lastname: Muller
authors.forename: Wei Xia
authors.initials: WX
authors.lastname: Ang
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.forename: Guido
authors.initials: G
authors.lastname: Franzoso
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004789:Enzyme Activation; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016259:Genes, myc; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D064593:Heterografts; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D059505:Telomere Homeostasis / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: C489428:Myc protein, mouse; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; C422952:telomerase RNA; D012313:RNA; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D019098:Telomerase; C509187:Tert protein, mouse