HSF1 activation by NF1 loss promotes stress adaptation and facilitates tumorigenesis.

  • Major finding: HSF1 activation by NF1 loss promotes stress adaptation and facilitates tumorigenesis.

  • Mechanism: Dysregulated RAS–MAPK signaling stabilizes HSF1 protein, which further augments MAPK activity.

  • Impact: Selective inhibition of HSF1 may suppress the growth and progression of NF1-deficient tumors.

Induction of a heat shock factor 1 (HSF1)–mediated transcriptional program is essential to maintain homeostasis and cell survival in response to a variety of stressors. This adaptive response also promotes oncogenic transformation, but the mechanisms by which HSF1 is activated in tumors are largely unknown. Using a short hairpin RNA library screen, Dai and colleagues identified loss of the tumor suppressor neurofibromin 1 (NF1) as a potent activator of HSF1 activity. In the absence of Nf1, the expression of HSF1 target genes was elevated in mouse embryonic fibroblasts (MEF). Furthermore, Nf1 depletion reduced ubiquitin-mediated degradation of HSF1, resulting in nuclear accumulation of active, phosphorylated HSF1 protein. HSF1 activation conferred increased tolerance to proteotoxic stress in Nf1-deficient MEFs, suggesting that HSF1 may facilitate tumorigenesis by enhancing cancer-cell survival under stress. Consistent with this notion, depletion of HSF1 in a mouse model of NF1 tumor predisposition syndrome resulted in prolonged tumor-free survival and a shift in tumor spectrum, supporting a role for HSF1 in NF1-associated disease. Phosphorylated, nuclear HSF1 was also detected in NF1-mutant human malignant peripheral nerve sheath tumor (MPNST) cell lines and in primary human MPNST samples. In addition, HSF1 ablation impaired the viability of MPNST cells in vitro, indicating a dependence on HSF1 activity for tumor growth. HSF1 activation was mediated by aberrant MAPK signaling induced by Nf1 loss; moreover, activated HSF1 was sufficient to further augment MAPK signaling in MPNST cells lacking NF1 via a feed-forward loop and enhanced the sensitivity of these cells to MEK inhibitors. These findings establish NF1 as an important modulator of the HSF1 adaptive stress response and support the development of HSF1 inhibitors to suppress the growth of NF1 malignancies.

Dai C, Santagata S, Tang Z, Shi J, Cao J, Kwon H, et al. Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis. J Clin Invest 2012 Sept 4 [Epub ahead of print].

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