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

Tamara Isermann, Özge Çiçek Şener, Adrian Stender, Luisa Klemke, Nadine Winkler, Albrecht Neesse, Jinyu Li, Florian Wegwitz, Ute M. Moll and Ramona Schulz-Heddergott ()
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Tamara Isermann: University Medical Center Göttingen
Özge Çiçek Şener: University Medical Center Göttingen
Adrian Stender: University Medical Center Göttingen
Luisa Klemke: University Medical Center Göttingen
Nadine Winkler: University Medical Center Göttingen
Albrecht Neesse: University Medical Center Göttingen
Jinyu Li: Stony Brook University
Florian Wegwitz: University Medical Center Göttingen
Ute M. Moll: University Medical Center Göttingen
Ramona Schulz-Heddergott: University Medical Center Göttingen

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24064-1

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