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Developmental priming of cancer susceptibility [DNA methylation array - d10earclips]

ABSTRACT: DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility ‘states’ in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

ORGANISM(S): Mus musculus

PROVIDER: GSE229030 | GEO | 2023/09/07

REPOSITORIES: GEO

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Project description:Human telomerase reverse transcriptase (hTERT) is a rate-limiting catalytic subunit of the enzyme telomerase, which plays a central role in maintaining replicative immortality in normal stem cells and many cancer cells. Mostly silenced in normal somatic cells, hTERT is reactivated in cancer commonly through highly recurrent hot spot point mutations in the hTERT promoter. Bladder cancer has a 60-70% hTERT promoter mutation prevalence, commonly at -124 bp from the translation start site, and this is associated with increased hTERT expression and poor patient prognosis. Identifying targetable signaling pathways that drive hTERT transcription from the mutant promoter could lead to therapies with reduced effects on normal progenitors. Here we describe a new platform that probes endogenous hTERT regulation by allele-specific insertion of GFP at either wild-type or mutant promoter allele within human bladder cancer cells harboring a heterozygous mutation. Using cells expressing the GFP-hTERT fusion protein, we performed a pooled CRISPR-Cas9 Kinome KO genetic screen to identify regulators of mutant hTERT promoter activity. We identified TRIM28 as an activator and TRIM24 as a suppressor of hTERT expression. Similar to hTERT, TRIM28 expression stratifies patient outcome and inhibits promotes cell growth both in vitro and in vivo, supporting their clinical relevance. TRIM28 and TRIM24 get recruited to the mutated promoter through GABPA, where TRIM24 interacts with TRIM28 and inhibits its activity as a transcriptional activator. TRIM28 phosphorylation causes its release from TRIM24 and activates hTERT transcription. mTOR phosphorylates TRIM28 through the mTORC1 complex leading to hTERT expression, while mTORC1 inhibition with rapamycin analog Ridaforolimus suppresses the phosphorylation and promoter binding of TRIM28, resulting in reduced hTERT expression and lower cell viability. This study uses a bespoke platform to identify a novel therapeutically tractable regulatory pathway for cancers harboring mutant hTERT promoters.

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Developmental priming of cancer susceptibility [DNA methylation array - d10earclips]

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