Inactivation of Heat Shock Factor Hsf4 Induces Cellular Senescence and Suppresses Tumorigenesis In Vivo

Abstract

Studies suggest that Hsf4 expression correlates with its role in cell growth and differentiation. However, the role of Hsf4 in tumorigenesis in vivo remains unexplored. In this article, we provide evidence that absence of the Hsf4 gene suppresses evolution of spontaneous tumors arising in p53- or Arf-deficient mice. Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes. Using mouse embryo fibroblasts deficient in the hsf4 gene, we have found that these cells exhibit reduced proliferation that is associated with induction of senescence and senescence-associated β-galactosidase (SA-β-gal). Cellular senescence in hsf4-deficient cells is associated with the increased expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins. Consistent with the cellular senescence observed in vitro, specific normal tissues of hsf4−/− mice and tumors that arose in mice deficient in both hsf4 and p53 genes exhibit increased SA-β-gal activity and elevated levels of p27 compared with wild-type mice. These results suggest that hsf4 deletion-induced senescence is also present in vivo. Our results therefore indicate that Hsf4 is involved in modulation of cellular senescence, which can be exploited during cancer therapy.

Heat shock factor 2 is associated with the occurrence of lung cancer by enhancing the expression of heat shock proteins

“…Among them, HSF1 has been associated with the occurrence of cancer (14). HSF4 is also associated with cancer, and inactivation of HSF4 induces cellular senescence and suppresses tumorigenesis in vivo (15). Thus, in the present study, the expression level of HSF2 in lung cancer was investigated and the cellular role of HSF2, including cell proliferation and cell migration, was characterized.…”

High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer

“…A potential role of HSF4 in stimulating cellular proliferation and differentiation has previously been reported . HSF4 deletion is associated with increased expression of cyclin‐dependent kinase inhibitors, p21 and p27 proteins in mouse embryo fibroblasts . In addition, HSF4 deletion also reduces cellular proliferation and induces senescence .…”

“…HSF4 deletion is associated with increased expression of cyclin‐dependent kinase inhibitors, p21 and p27 proteins in mouse embryo fibroblasts . In addition, HSF4 deletion also reduces cellular proliferation and induces senescence . In p53‐ or Arf‐deficient mice, the absence of the HSF4 gene could suppress evolution of spontaneous tumors .…”

“…In addition, HSF4 deletion also reduces cellular proliferation and induces senescence . In p53‐ or Arf‐deficient mice, the absence of the HSF4 gene could suppress evolution of spontaneous tumors . In human breast cancer cells, HSF4/HSF2 can cooperatively bind to heat shock element sequences in the HIF‐1α promoter region and maintain its expression, thereby activating the downstream genes of canonical HIF‐1α signaling pathways, such as VEGF .…”

Targeted Deletion of Hsf1, 2, and 4 Genes in Mice

“…Contribution of other Hsfs to tumorigenesis remains less explored. We have shown that deletion of Hsf4-deficient mice are resistant to p53-loss-induced lymphomas 22 . Hsf2 expression has been shown to be reduced in number tumor types and knockdown of Hsf2 increases the invasion ability of prostate cancer cell line 23 .…”