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Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion due to R-loop accumulation IV

ABSTRACT: Kras is the most commonly mutated oncogene in human cancer and mutant Kras is responsible for over 90% of pancreatic ductal adnocarcinoma (PDAC), the most leath cancer. Here, we identified that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult panreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin and therby abbarrent R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We also demonstrate that the sepcific demand for PAF1C by cancer cells is due to the global activation of enhancers and thus eRNA transcription during tumorigenesis. The work provides a novel insight in how transcription addiction is caused during tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE217744 | GEO | 2023/11/01

REPOSITORIES: GEO

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Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion due to R-loop accumulation III

Project description:Kras is the most commonly mutated oncogene in human cancer and mutant Kras is responsible for over 90% of pancreatic ductal adnocarcinoma (PDAC), the most leath cancer. Here, we identified that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult panreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin and therby abbarrent R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We also demonstrate that the sepcific demand for PAF1C by cancer cells is due to the global activation of enhancers and thus eRNA transcription during tumorigenesis. The work provides a novel insight in how transcription addiction is caused during tumorigenesis.

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Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion due to R-loop accumulation I

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Project description:Mutations in members of the SWI/SNF chromatin remodeling family are common events in human cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the pancreas of mice in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.

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