Charlie Norwood VA Medical Center, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
Mol Cancer Res. 2012 Apr;10(4):523-34. doi: 10.1158/1541-7786.MCR-11-0530. Epub 2012 Feb 21.
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.
研究表明，Hsf4 的表达与其在细胞生长和分化中的作用相关。然而，Hsf4 在体内肿瘤发生中的作用仍未被探索。在本文中，我们提供的证据表明，Hsf4 基因的缺失抑制了 p53 或 Arf 缺失小鼠自发肿瘤的演进。此外，hsf4 的缺失通过显著抑制通常在大多数缺乏 p53 或 Arf 肿瘤抑制基因的小鼠中观察到的淋巴瘤的发展，改变了肿瘤谱。使用缺乏 hsf4 基因的小鼠胚胎成纤维细胞，我们发现这些细胞表现出增殖减少，这与衰老和衰老相关的 β-半乳糖苷酶（SA-β-gal）的诱导有关。hsf4 缺陷细胞中的细胞衰老与周期蛋白依赖性激酶抑制剂 p21 和 p27 蛋白的表达增加有关。与体外观察到的细胞衰老一致，hsf4(-/-) 小鼠的特定正常组织和同时缺失 hsf4 和 p53 基因的小鼠中出现的肿瘤表现出比野生型小鼠更高的 SA-β-gal 活性和 p27 水平升高。这些结果表明，hsf4 缺失诱导的衰老也存在于体内。因此，我们的结果表明 Hsf4 参与了细胞衰老的调节，这在癌症治疗中可以得到利用。
