A hallmark in the pathogenesis of cancer is increased expression of heat shock proteins (Hsps) and other molecular chaperones;this is considered to be an adaptive response to enhanced tumor cell survival. Hsp expression is regulated at multiple levels, but heat shock transcription factors (Hsfs) are the primary regulators of stress-inducible expression in eukaryotic cells. Although the role of Hsf and Hsps in protecting organisms from a broad range of pathological conditions has been widely studied, their potential roles in malignancy are largely unexplored. Experimental evidence from our laboratory and others have uncovered in mouse models a surprising and critical role of Hsf1 is tumorigenesis. However, the contribution of other Hsfs, such as Hsf4, in oncogenesis remains elusive. During the last funding period of this grant, we created hsf4-/- mice to study its physiological function in vivo. We interestingly discovered that an Hsf4-mediated response plays a critical role in tumor growth and progression: Intriguingly, this response differentially impacts the tumorigenesis by either supporting or inhibiting tumor growth, depending on the model under investigation. In this grant utilizing our mutant mice models we will critically evaluate the following hypothesis: The opposing effects of Hsf4 in oncogenesis reflects its prominent function in orchestrating a network of cellular functions, including promotion of myoblast cell differentiation, which preferentially inhibits rhabdomyosarcomas (RMS) development as well as modulating tumor microenvironment components that enhance hepatocellular carcinoma (HCC) initiation and progression. We propose to pursue the following specific aims:
Aim I. To investigate how hsf4 control of cellular differentiation impacts tumorigenesis in mouse models of spontaneous tumorigenesis.
Aim II. To investigate how hsf4 control of cellular differentiation and the microenvironment impacts tumorigenesis in mouse models of a chemical-induced cancer.
Aim III. To investigate Hsf4 expression and function in human RMS cell lines and primary tumors. The proposed studies will help to achieve a better understanding of the fundamental cellular processes in which Hsfs and general molecular chaperones engage to promote tumor growth, and may help to develop strategies to modulate specific chaperone-dependent host pathways as a therapeutic approach to combat human cancers and other relevant diseases. PUBLIC HEALTH RELAVANCE: The heat shock transcription factor Hsf4 exhibits properties of a tumor suppressor gene and its functional loss is associated with acceleration of tumorigenesis demonstrated in mouse models. The fact that Hsf4 expression is also lost in human tumors;it is our proposal that Hsf4 loss may promote tumorigenesis in human.
|Eroglu, Binnur; Min, Jin-Na; Zhang, Yan et al. (2014) An essential role for heat shock transcription factor binding protein 1 (HSBP1) during early embryonic development. Dev Biol 386:448-60|
|Eroglu, Binnur; Kimbler, Donald E; Pang, Junfeng et al. (2014) Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury. J Neurochem 130:626-41|
|Jin, Xiongjie; Eroglu, Binnur; Cho, Wonkyoung et al. (2012) Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo. Mol Cancer Res 10:523-34|
|Jin, Xiongjie; Eroglu, Binnur; Moskophidis, Demetrius et al. (2011) Targeted deletion of Hsf1, 2, and 4 genes in mice. Methods Mol Biol 787:1-20|
|Antonov, Alexander S; Antonova, Galina N; Munn, David H et al. (2011) ýýVýý3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-ýýB activation. J Cell Physiol 226:469-76|
|Jin, Xiongjie; Moskophidis, Demetrius; Mivechi, Nahid F (2011) Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metab 14:91-103|
|Hu, Yanzhong; Mivechi, Nahid F (2011) Promotion of heat shock factor Hsf1 degradation via adaptor protein filamin A-interacting protein 1-like (FILIP-1L). J Biol Chem 286:31397-408|
|Eroglu, Binnur; Moskophidis, Demetrius; Mivechi, Nahid F (2010) Loss of Hsp110 leads to age-dependent tau hyperphosphorylation and early accumulation of insoluble amyloid beta. Mol Cell Biol 30:4626-43|
|Jin, Xiongjie; Moskophidis, Demetrius; Hu, Yanzhong et al. (2009) Heat shock factor 1 deficiency via its downstream target gene alphaB-crystallin (Hspb5) impairs p53 degradation. J Cell Biochem 107:504-15|
|Huang, Lei; Min, Jin-Na; Masters, Shane et al. (2007) Insights into function and regulation of small heat shock protein 25 (HSPB1) in a mouse model with targeted gene disruption. Genesis 45:487-501|