Chromatin dysregulation by mutant p53

The TP53 gene, which encodes a DNA sequencedependent transcriptional regulator, is arguably the most frequently mutated gene in human cancer. Whereas wildtype p53 is restricted to its cognate DNA binding sites, mutant p53 (via mutation in the DNA binding domain) is no longer constrained to specific genomic sites. Mutant p53 proteins therefore cannot effectively mediate wildtype p53 tumor suppressive transcriptional programs, thereby enabling permissive tumor growth. Nevertheless, missense mutant forms of p53 can promiscuously alter the transcriptome of the cells they inhabit through association with transcription factors and other chromatin regulators. A global mechanism that could explain mutant p53dependent gene expression changes would be a useful step in elucidating mutant p53 gain of oncogenic function. In a recent issue of Genes & Development, we reported that mutant p53 stimulates expression of the VEGFR2 receptor tyrosine kinase (RTK), thereby stimulating oncogenic growth and malignant characteristics of breast cancer cells [1]. Augmented transcription of VEGFR2 was shown to be the result of mutant p53 association with the SWI/SNF chromatin remodeling complex at the VEGFR2 promoter to enhance SWI/SNF-dependent chromatin remodeling. We further showed that mutant p53 functions with SWI/SNF to mediate >40% of mutant p53-dependent gene expression changes, providing the first evidence that mutant p53 influences promoter conformation and causes global gene expression changes through cooperation with a chromatin remodeling complex [1]. VEGFR2 was selected as a model gene to study promoter-specific effects of mutant p53 because it is a candidate proto-oncogene and receptor tyrosine kinase with cell signaling functions similar to other known mutant p53-regulated RTKs such as EGFR, IGF1R, MET and PDGFRB (discussed in [1]). Further, wild-type p53 suppresses tumor neoangiogenesis through multiple mechanisms including repression of VEGF and increased degradation of HIF1A [4] and it is often the case that there is an oppositional relationship between genes regulated by wild-type and mutant p53. One implication is that cells with wild-type p53 actively antagonize oncogene signaling (a known phenomenon) while cancer cells with mutant p53 actively promote oncogene signaling. Indeed, we found that mutant p53 enhances VEGFR2 transcription to such an extent that the breast cancer cell lines we tested are dependent on VEGFR2 signaling for optimal growth and cellular migration [8]. We also reported intriguing clinical trial data suggesting that patients with mutant p53-expressing breast tumors respond better than those with wild-type p53 tumors to anti-VEGF treatment (bevacizumab) although these results would need further statistical validation [1]. We speculate that mutation in p53 coincides with the angiogenic switch, as p53 mutation can simultaneously de-repress VEGF expression and stimulate Editorial