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

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.

Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members

“…An algorithm-based study predicts the presence of p53-responsive elements in the human DNAJA1/HDJ2's promoter, which is confirmed by chromatin-immunoprecipitation studies using MCF7 cells (wtp53) [77]. Moreover, a recent report shows that wtp53 indirectly represses mRNA expression of DNAJA1/HDJ2 by inhibiting phosphorylation of heat-shock factor 1 (HSF1), the master regulator of the proteotoxic stress response [78]. However, DNAJA1/HDJ2 levels are unchanged following exogenous introduction of wtp53 in mutp53-knockout HN31 cells [65].…”

Skeletal muscle HSF1 prevents insulin resistance by improving glucose utilization

“…Previous studies have reported that constitutively active HSF1 in pancreatic islet cells enhances glucose‐induced insulin secretion, 9,12,13 but their specific contribution to insulin action still needs to be explored. Moreover, HSF1 regulates several non‐heat shock protein genes that support oncogenic processes, including cell cycle regulation, signaling, metabolism, adhesion, and translation 14–18 . Skeletal muscles are the main site of insulin‐stimulated glucose utilization; however, it is unclear whether and how muscle HSF1 affects glucose metabolism.…”

“…Moreover, HSF1 regulates several non-heat shock protein genes that support oncogenic processes, including cell cycle regulation, signaling, metabolism, adhesion, and translation. [14][15][16][17][18] Skeletal muscles are the main site of insulin-stimulated glucose utilization; however, it is unclear whether and how muscle HSF1 affects glucose metabolism. In the present study, we investigated the role of HSF1 in muscle glucose metabolism.…”

HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia

“…Among the mechanisms that result in increased levels of nuclear HSF1, in a broad range of cancers, include amplification of the HSF1 gene located within chromosome 8q24.3, reduced expression of the HSF1 degradation F box E3 ligase Fbxw7, activation by loss of p53 and increased HSF1 transcription by oncogenic signaling pathways such as NOTCH signaling 30 , 80 – 82 . Other potential contributing factors are the accumulation of the mutant cancer proteome and rapid proliferation of cancer cells, which may select for increased levels and activity of HSF1 via additional mechanisms.…”