Unknown,Transcriptomics,Genomics,Proteomics

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Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (ChIP-Seq)


ABSTRACT: Constitutively active MYC and reactivated telomerase often co-exist in cancers. While the reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with co-factors, confers several growth advantages to cancer cells. However, it is unclear which co-factors sustain elevated MYC activity in tumours . Here, we identify TERT, the catalytic subunit of telomerase, as a novel regulator of MYC stability in cancers. Binding of TERT to MYC stabilizes its levels on chromatin, contributing to either activation or repression of its target genes. Mechanistically, TERT regulates MYC ubiquitination and stability, and this effect of TERT is independent of its role on telomeres. Genetic inhibition and knocking out of TERT phenocopied the loss of MYC, resulting in reduced disease burden of early- and late-stage MYC-driven murine lymphomas. Conversly, the ectopic expression of TERT could substitute for reduced MYC in these functions. Finally we show that TERT null mice, unlike Terc null mice, show delayed onset of MYC induced lymphomagenesis. Accordingly, inhibiting TERT function in primary human leukemia cells blocked the expression of MYC targets, while Terc depletion had no effects . Based on our data, we conclude that the re-expression of TERT, a direct MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis. ChIP was performed using anti-MYC (sc-764) in primary lymphoma cells from Eµ-Myc;Tert -/- mice, Eµ-Myc;Tert +/+ mice, or in P493 cells treated with shTert, P493 shTerc and shControl.

ORGANISM(S): Mus musculus

SUBMITTER: Julius Müller 

PROVIDER: E-GEOD-60223 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity.

Koh Cheryl M CM   Khattar Ekta E   Leow Shi Chi SC   Liu Chia Yi CY   Muller Julius J   Ang Wei Xia WX   Li Yinghui Y   Franzoso Guido G   Li Shang S   Guccione Ernesto E   Tergaonkar Vinay V  

The Journal of clinical investigation 20150420 5


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 "hallmar  ...[more]

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