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MST-312: a telomerase inhibitor effectively blocking MYC oncogenic functions [array]

ABSTRACT: Reactivation of the telomerase reverse transcriptase subunit, TERT, is linked to tumourigenesis due to well-documented telomere-dependent and independent functions. The aim of this study was to investigate the effect of the telomerase inhibitor, MST-312, on TERT functions, focusing in particular, on its effects on MYC stabilty and MYC-regulated pathways, in order to assess its potential as a therapeutic agent. We demonstrate that MST-312 reduces MYC levels in cancer cells, leading to reduced MYC levels on chromatin, and subsequently affecting the MYC-regulated transcriptional program. As a result, MST-312 treatment increases the survival of lymphoma-bearing mice. Mechanistically, MST-312 affects the conformation of TERT, leading to TERT/Terc dissociation, and the subsequent loss of both its telomere-dependent and independent functions. Based on the presented data, we conclude that MST-312 treatment is a promising therapeutic strategy, in particular, in MYC-driven tumorus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77014 | GEO | 2020/01/01

REPOSITORIES: GEO

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MST-312: a telomerase inhibitor effectively blocking MYC oncogenic functions [ChIP-Seq]

Project description:Reactivation of the telomerase reverse transcriptase subunit, TERT, is linked to tumourigenesis due to well-documented telomere-dependent and independent functions. The aim of this study was to investigate the effect of the telomerase inhibitor, MST-312, on TERT functions, focusing in particular, on its effects on MYC stabilty and MYC-regulated pathways, in order to assess its potential as a therapeutic agent. We demonstrate that MST-312 reduces MYC levels in cancer cells, leading to reduced MYC levels on chromatin, and subsequently affecting the MYC-regulated transcriptional program. As a result, MST-312 treatment increases the survival of lymphoma-bearing mice. Mechanistically, MST-312 affects the conformation of TERT, leading to TERT/Terc dissociation, and the subsequent loss of both its telomere-dependent and independent functions. Based on the presented data, we conclude that MST-312 treatment is a promising therapeutic strategy, in particular, in MYC-driven tumorus.

2020-01-01 | GSE77061 | GEO

MST-312: a telomerase inhibitor effectively blocking MYC oncogenic functions

Project description:MST-312: a telomerase inhibitor effectively blocking MYC oncogenic functions

| PRJNA309377 | ENA

Gene expression changes by telomere shortening in human colonic organoids

Project description:Gene expression changes of UC-model organoids derive from human colon indcued by telomere enlongation was assessed by Madecassoside treatemt (telomerase activator). Gene expression changes of human colon organoids induced by telomere shortening was assessd by MST-312 treatment (telomerase inhibitor).

2021-06-24 | GSE175994 | GEO

Genome-wide TNFM-NM-1-induced p65 binding before and after telomerase inhibition in HeLa cells

Project description:Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to analyze the effect of telomerase inhibition on TNFM-NM-1-induced genome-wide p65 binding in HeLa cells. By obtaining over 40 million uniquely mappable reads per sample from ChIP-seq, maps for TNFM-NM-1-induced p65 binding in absence and presence of an hTERT inhibitor, MST-312, were generated. As expected, TNFM-NM-1 treatment significantly increased genome-wide p65 occupancy. Interestingly, when cells were treated with MST-312 prior to TNFM-NM-1 stimulation, the number of p65 binding sites was reduced. In addition, some binding sites, including important p65 targets like IL6 and TNF, showed a reduced p65 occupancy with a minimum fold change of 1.5, after MST-312 exposure. Taken together, our ChIP-seq data indicate that telomerase is required for optimal p65 binding at a small proportion of p65 target sites upon inflammatory stimuli. Examination of p65 binding in HeLa cells in absence and presence of TNFM-NM-1 and MST-312.

2012-11-26 | E-GEOD-41100 | biostudies-arrayexpress

Homo sapiens

Project description:MST-312: a telomerase inhibitor effectively blocking MYC oncogenic functions [array]

| PRJNA309283 | ENA

Homo sapiens

Project description:MST-312: a telomerase inhibitor effectively blocking MYC oncogenic functions [ChIP-Seq]

| PRJNA309378 | ENA

Genome-wide TNFα-induced p65 binding before and after telomerase inhibition in HeLa cells

Project description:Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to analyze the effect of telomerase inhibition on TNFα-induced genome-wide p65 binding in HeLa cells. By obtaining over 40 million uniquely mappable reads per sample from ChIP-seq, maps for TNFα-induced p65 binding in absence and presence of an hTERT inhibitor, MST-312, were generated. As expected, TNFα treatment significantly increased genome-wide p65 occupancy. Interestingly, when cells were treated with MST-312 prior to TNFα stimulation, the number of p65 binding sites was reduced. In addition, some binding sites, including important p65 targets like IL6 and TNF, showed a reduced p65 occupancy with a minimum fold change of 1.5, after MST-312 exposure. Taken together, our ChIP-seq data indicate that telomerase is required for optimal p65 binding at a small proportion of p65 target sites upon inflammatory stimuli.

2012-11-26 | GSE41100 | GEO

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

Project description: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.

2015-04-23 | E-GEOD-60223 | biostudies-arrayexpress

Telomerase subunit TERT regulates MYC stability independent of its role on telomeres (array)

Project description: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 tumors . 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. P493 cells were stably infected with the following viruses: pLKO shControl and pLKO shTERT.

2015-04-23 | E-GEOD-60175 | biostudies-arrayexpress

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

2015-04-23 | GSE60223 | GEO

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