Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity
File(s)- JCI79134.pdf (4.63 MB)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2015-05-01
Date Acceptance
2015-03-12
Citation
Journal of Clinical Investigation, 2015, 125 (5), pp.2109-2122
ISSN
1558-8238
Publisher
American Society for Clinical Investigation
Start Page
2109
End Page
2122
Journal / Book Title
Journal of Clinical Investigation
Volume
125
Issue
5
Copyright Statement
© 2015 American Society for Clinical Investigation
Sponsor
Cancer Research UK
Identifier
https://www.jci.org/articles/view/79134
Grant Number
15115
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
C-MYC
TRANSGENIC MICE
IN-VIVO
CATALYTIC SUBUNIT
GENE-EXPRESSION
RIBOSOMAL DNA
HUMAN GENOME
CANCER
CHROMATIN
BINDING
Publication Status
Published
Date Publish Online
2015-04-20