Heat-shock factor 1 both positively and negatively affects cellular clonogenic growth depending on p53 status

We examined the role of HSF1 in relation to cancer cell clonogenicity, an important attribute of cancer cells. Ectopic expression or HSF1 knockdown demonstrated that HSF1 positively regulated cancer cell clonogenic growth. Furthermore, knockdown of mutant p53 indicated that HSF1 actions were mediated via a mutant p53 dependent mechanism. To more specifically examine this relationship we ectopically co-expressed mutant p53R273H and HSF1 in the human mammary epithelial cell line, MCF10A. Surprisingly, within this cellular context, HSF1 inhibited clonogenicity. However, upon specific knockdown of endogenous wild-type p53, thus leaving mutant p53R273H expression intact, HSF1 was observed to greatly enhance clonogenic growth of the cells indicating that HSF1 suppressed clonogenicity via wild-type p53. To confirm this we ectopically expressed HSF1 in non-transformed and H-RasV12 transformed MCF10A cells. As expected, HSF1 significantly reduced clonogenicity, altering wild-type p53 target gene expression levels consistent with a role of HSF1 increasing wild-type p53 activity. In support of this finding, knockdown of wild-type p53 negated the inhibitory effects of HSF1 expression. We thus show that HSF1 can impact upon clonogenic growth in a p53 context dependent manner, and can act via both mutant and wild-type p53 to bring about divergent effects upon clonogenicity. These findings have important implications for our understanding of HSF1’s divergent roles in cancer cell grow...
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Cell Source Type: research