Heat Shock Factor 1 (HSF1) Controls Chemoresistance and Autophagy through Transcriptional Regulation of Autophagy-related Protein 7 (ATG7)

• Published in: The Journal of biological chemistry Vol. 288; no. 13; pp. 9165 - 9176
• Main Authors: Desai, Shruti, Liu, Zixing, Yao, Jun, Patel, Nishant, Chen, Jieqing, Wu, Yun, Ahn, Erin Eun-Young, Fodstad, Oystein, Tan, Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.03.2013; American Society for Biochemistry and Molecular Biology
• Subjects: ATG7; Autophagy; Autophagy-Related Protein 7; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer; Carboplatin - pharmacology; Cell Biology; Cell Death; Cell Line, Tumor; Chemoresistance; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm; Female; Flow Cytometry - methods; Gene Expression Regulation; Heat Shock Transcription Factors; Heat Shock-independent Autophagy; HSF1; Humans; Luciferases - metabolism; Microscopy, Fluorescence - methods; Prognosis; RNA, Small Interfering - metabolism; Transcription Factors - metabolism; Transcription Regulation; Transcription, Genetic; Ubiquitin-Activating Enzymes - metabolism; Transcription Regulation; Cell Death; Chemoresistance; HSF1; Heat Shock-independent Autophagy; Autophagy; ATG7; Cancer
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.422071

Heat shock factor 1 (HSF1), a master regulator of heat shock responses, plays an important role in tumorigenesis. In this study we demonstrated that HSF1 is required for chemotherapeutic agent-induced cytoprotective autophagy through transcriptional up-regulation of autophagy-related gene ATG7. Interestingly, this is independent of the HSF1 heat shock response function. Treatment of cancer cells with the FDA-approved chemotherapeutic agent carboplatin induced autophagy and growth inhibition, which were significantly increased upon knockdown of HSF1. Mechanistic studies revealed that HSF1 regulates autophagy by directly binding to ATG7 promoter and transcriptionally up-regulating its expression. Significantly, breast cancer patient sample study revealed that a higher ATG7 expression level is associated with poor patient survival. This novel finding was further confirmed by analysis of two independent patient databases, demonstrating a prognostic value of ATG7. Furthermore, a strong positive correlation was observed between levels of HSF1 and ATG7 in triple-negative breast cancer patient samples, thus validating our in vitro findings. This is the first study identifying a critical role for HSF1 in controlling cytoprotective autophagy through regulation of ATG7, which is distinct from the HSF1 function in the heat shock response. This is also the first study demonstrating a prognostic value of ATG7 in breast cancer patients. These findings strongly argue that combining chemotherapeutic agents with autophagy inhibition by repressing HSF1/ATG7 axis represents a promising strategy for future cancer treatment. Background: HSF1 influences chemoresistance in cancer. Results: Chemotherapy activates HSF1, leading to direct transcriptional regulation of autophagy related gene, ATG7. In vitro findings are supported by patient sample study. Conclusion: HSF1 regulates cytoprotective, heat shock-independent autophagy by directly regulating ATG7, which plays an important role in chemoresistance. Significance: Identification of novel HSF1/ATG7 axis in chemoresistance strongly supports development of robust combination therapies, targeting it in cancer.