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Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

ABSTRACT: Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

PROVIDER: PRJEB44756 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR5882023_1.fastq.gz	Fastqsanger.gz
	ERR5882023_2.fastq.gz	Fastqsanger.gz
	ERR5882024_1.fastq.gz	Fastqsanger.gz
	ERR5882024_2.fastq.gz	Fastqsanger.gz
	ERR5882025_1.fastq.gz	Fastqsanger.gz

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RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

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Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:p53LOH in murine CRC organoids de-represses HSF1 activity and triggers mutp53-driven invasion.

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Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity.

Project description:The vast majority of human tumors with p53 mutations undergo loss of the remaining wildtype p53 allele (loss-of-heterozygosity, p53LOH). p53LOH has watershed significance in promoting tumor progression. However, driving forces for p53LOH are poorly understood. Here we identify the repressive WTp53-HSF1 axis as one driver of p53LOH. We find that the WTp53 allele in AOM/DSS chemically-induced colorectal tumors (CRC) of p53R248Q/+ mice retains partial activity and represses heat-shock factor 1 (HSF1), the master regulator of the proteotoxic stress response (HSR) that is ubiquitously activated in cancer. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining CRC tumors, tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 program. Mechanistically, retained WTp53 activates CDKN1A/p21, causing cell cycle inhibition and suppression of E2F target MLK3. MLK3 links cell cycle with the MAPK stress pathway to activate the HSR response. In p53R248Q/+ tumors WTp53 activation by constitutive stress represses MLK3, thereby weakening the MAPK-HSF1 response necessary for tumor survival. This creates selection pressure for p53LOH which eliminates the repressive WTp53-MAPK-HSF1 axis and unleashes tumor-promoting HSF1 functions, inducing mutp53 stabilization enabling invasion.

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RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:Mice with colonic tumors (chemically induced by AOM/DSS) were treated with Nutlin or control vehicle solution to analyze p53 target gene expression in vivo.

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Project description:Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controlling expression of heat shock proteins (HSPs) and cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis, but dependent on activation of the p53-p21 pathway, partly because of increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, an inhibitor of HSP70 family proteins increased proteotoxicity and suppressed cell growth, but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway due to reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contribute to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS.

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