Heat Shock Factor 1 (HSF1), a master regulator of heat shock response, plays an important role in tumorigenesis. In this study we demonstrate that HSF1 is required for chemotherapeutic agents induced cytoprotective autophagy and Endoplasmic Reticulum (ER) stress response. HSF1 can transcriptionally regulate autophagy related gene ATG7 and ER membrane protein IRE1α. Interestingly, most of this regulation is independent of HSF1's heat shock function.

Treatment of cancer cells with FDA approved chemotherapeutic agent induced autophagy which was significantly decreased upon HSF1 knockdown. Mechanistic studies revealed that HSF1 regulates autophagy by directly binding to the ATG7 promoter and transcriptionally upregulating its expression. HSF1 also may play a role in regulating autophagy by modulating levels of phosphorylated AMPK, a key protein that can trigger autophagy. Thus HSF1 regulates the process of autophagy in a multi-pronged manner, through regulation of key autophagy protein as well as regulation of key inducer of autophagy. Furthermore, a strong positive correlation was observed between levels of HSF1 and ATG7 in breast cancer patient samples, thus validating our in vitro findings. Similarly, knockdown of HSF1 reduced the induction of ER stress response by chemotherapeutic agents. Mechanistic studies have revealed that HSF1 regulated cytoprotective ER stress response by directly regulating IRE1α expression and sustained activation. IRE1α, a resident ER protein, is a key sensor of ER stress. It activates Xbp1 leading to expression of protein chaperone genes that help alleviate the ER stress response. This HSF1/IRE1α pathway was further validated in cancer patients by immunohistochemistry staining of breast cancer patient tissue array.

This study identifies a critical role for HSF1 in controlling cytoprotective stress response pathways of autophagy and ER stress response in tumor cells. HSF1 does this by not only regulating transcription of key proteins required in these pathways but also by regulating activation of key inducers of these pathways. The findings from this study can be further used to design more robust treatment strategies for breast cancer patients thus improving their prognosis.

Citation Format: Shruti Desai, Ming Tan. Role of HSF1 in chemotherapy-induced autophagy and endoplasmic reticulum stress response in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B55.

©2016 American Association for Cancer Research.
2016