Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity
Cheryl M. Koh, Ekta Khattar, Shi Chi Leow, Chia Yi Liu, Julius Muller, Wei Xia Ang, Yinghui Li, Guido Franzoso, Shang Li, Ernesto Guccione, Vinay Tergaonkar
Cheryl M. Koh, Ekta Khattar, Shi Chi Leow, Chia Yi Liu, Julius Muller, Wei Xia Ang, Yinghui Li, Guido Franzoso, Shang Li, Ernesto Guccione, Vinay Tergaonkar
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Research Article Oncology

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

Cheryl M. Koh, Ekta Khattar, Shi Chi Leow, Chia Yi Liu, Julius Muller, Wei Xia Ang, Yinghui Li, Guido Franzoso, Shang Li, Ernesto Guccione, Vinay Tergaonkar

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Figure 1

Effect of acute depletion of TERT on MYC-driven lymphomas in vivo.

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Effect of acute depletion of TERT on MYC-driven lymphomas in vivo. (A) W...
(A) Western blots showing levels of TERT, MYC, and actin in different tissues of EμMYC mice. (B) Kaplan-Meier survival analysis for mice xenografted with shControl, shTERT-A, shTERT-B, ectopic TERT, shTERT-A + ectopic TERT, shTERT-B + ectopic TERT, or shTerc EμMYC primary lymphoma cells. P < 0.01, shControl vs. shTERT-A and shTERT-B; P > 0.05, shControl vs. shTerc, TERT, shTERT-A + TERT, and shTERT-B + TERT. Weights of (C) tumors and (D) spleens of mice in B 1 month following transplant. Each dot represents an individual recipient mouse. The horizontal bars represent the mean. (E) P493 cells infected with shControl, shTERT1, shTERT2, shTERT3, TERT WT, TERT DN, shTERT3 + TERT WT, shTERT3 + TERT DN, and shTerc were xenografted into SCID recipient mice. P < 0.01, shControl vs. shTERT1, shTERT2, shTERT3; P > 0.05, shControl vs. shTERC; P < 0.01, shTERT3 vs. shTERT3 + TERT WT and shTERT3 + TERT DN. Survival analysis was carried out using the Kaplan-Meier method with log-rank test. The number of animals is indicated by the graph. One-way ANOVA with Dunnett’s multiple comparison test was used to compare differences between the various groups and shControl. *P < 0.05, **P < 0.01, versus control.