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RNA Polymerase I activity prevents terminal differentiation and growth arrest in colorectal cancer and induce vulnerability for senolytics

ABSTRACT: RNA Polymerase I activity prevents terminal differentiation and growth arrest in colorectal cancer and induce vulnerability for senolytics

PROVIDER: PRJNA842078 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19389331.fastq.gz	Fastqsanger.gz
	SRR19389332.fastq.gz	Fastqsanger.gz
	SRR19389333.fastq.gz	Fastqsanger.gz
	SRR19389334.fastq.gz	Fastqsanger.gz
	SRR19389335.fastq.gz	Fastqsanger.gz

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RNA Polymerase I activity prevents terminal differentiation and growth arrest in colorectal cancer and induce vulnerability for senolytics

Project description:Loss of the tumor suppressor APC, which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces expression of RNA polymerase I (RNAPOL1) transcription machinery and subsequently upregulates rDNA transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity and induces a disbalance of ribosomal proteins. CX5461-induced growth arrest is irreversible, and exhibits features of senescence as well as terminal differentiation. Mechanistically, CX5461 promotes differentiation in a MIZ1- and Rb-dependent manner. In addition, inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents.

2022-05-31 | GSE204749 | GEO

RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells.

Project description:Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

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Project description:The discovery of effective senolytics offers a promising approach for treating many age-related diseases. In this study, we employed a phenotypic drug discovery approach, combining drug screening and drug design, to identify and develop novel senolytic agents based on the flavonoid fisetin. We successfully developed two novel flavonoid analogs, SR29384 and SR31133, which demonstrated significantly enhanced senolytic activities compared to fisetin. These analogs showed broad-spectrum efficacy in eliminating various senescent cell types, reducing tissue senescence, extending healthspan in mice, and prolonging lifespan in Drosophila. Through RNA sequencing, machine learning, and computational screening, our mechanistic studies suggest that these novel flavonoid senolytics may target PARP1, BCL2L1, and CDK2 to induce senescent cell death.

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Hotspot mutations induce metabolic reprogramming and vulnerability to serine deprivation

Project description:Cancer-associated mutations in the spliceosome gene create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we provide evidence that aberrant splicing by mutant alters the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also find that mutant induces vulnerability to deprivation of the nonessential amino acid serine, which is mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability is manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice is able to inhibit the growth ofMUT xenografts. These findings describe a novel role for mutations in altered energy metabolism, and they offer a new therapeutic strategy againstMUT cancers.

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