The Heat Shock Transcription Factor HSF1 Induces Ovarian Cancer Epithelial-Mesenchymal Transition in a 3D Spheroid Growth Model

Abstract

Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. The proteotoxic stress-responsive transcription factor HSF1 is frequently overexpressed in a variety of cancers and is vital to cellular proliferation and invasion in some cancers. Upon analysis of various patient data sets, we find that HSF1 is frequently overexpressed in ovarian tumor samples. In order to determine the role of HSF1 in ovarian cancer, inducible HSF1 knockdown cell lines were created. Knockdown of HSF1 in SKOV3 and HEY ovarian cancer cell lines attenuates the epithelial-to-mesenchymal transition (EMT) in cells treated with TGFβ, as determined by western blot and quantitative RT-PCR analysis of multiple EMT markers. To further explore the role of HSF1 in ovarian cancer EMT, we cultured multicellular spheroids in a non-adherent environment to simulate early avascular tumors. In the spheroid model, cells more readily undergo EMT; however, EMT inhibition by HSF1 becomes more pronounced in the spheroid model. These findings suggest that HSF1 is important in the ovarian cancer TGFβ response and in EMT.

FAM3C‐YY1 axis is essential for TGFβ‐promoted proliferation and migration of human breast cancer MDA‐MB‐231 cells via the activation of HSF1

“…This study revealed that HSF1 is a direct target gene of YY1, which induces HSF1 gene transcription. 45,46 Interestingly, although YY1-HSF1 pathway plays an important F I G U R E 8 FAM3C-YY1-HSF1 axis was activated in human breast cancer tissues. For the first time, our findings revealed that these important molecules are coordinated to promote the proliferation and migration of breast cancer cells.…”

“…New FAM3C-YY1 pathway also provides an explanation for the findings that TGFβ induces HSF1 expression with unclear mechanism in ovarian and breast cancer cells. 45,46 Interestingly, although YY1-HSF1 pathway plays an important F I G U R E 8 FAM3C-YY1-HSF1 axis was activated in human breast cancer tissues. (A-C) Immunohistochemical staining revealed that FAM3C (A), YY1 (B) and HSF1 (C) protein levels were increased in breast cancer tissues when compared normal breast tissues.…”

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…Indeed, it was demonstrated that HSF1 promotes TGFβ-induced EMT, tumorigenesis, and metastases in a murine breast cancer model [161]; the EMT-promoting mechanism was due to HSF1-mediated stimulation of the RAS/RAF/MEK/ERK1/2 signaling pathway. Additionally, HSF1 was found to be required for EMT in ovarian cancer (including a spheroid growth model) [162], hepatocellular carcinoma [163], and pancreatic cancer [164]. In the latter case, the abnormal HSF1 activation (phosphorylation) resulting in EMT induction in pancreatic cancer cells was correlated with the failure of AMPK activation in pancreatic tumors [164].…”

Proteomics analysis of proteins interacting with heat shock factor 1 in squamous cell carcinoma of the cervix

“…Upon activation by a variety of stimuli such as heat shock, infection and heavy metal toxicity, HSF1 forms trimers, translocates into the nucleus and induces various heat shock proteins (HSPs) by binding to heat shock elements (HSEs) on HSP promoters (4,5). Accumulating evidence has suggested that HSF1 is a powerful modifier of carcinogenesis; HSF1 levels are elevated in several cancers, including breast (6), ovarian (7) and cervical cancer (8). Activated or elevated HSF1 is often associated with resistance to chemotherapy drugs or poor prognosis (9).…”