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

Ming Tan,Nishant Patel,Oystein Fodstad,Shruti Desai,Jun Yao,Erin Eun-Young Ahn,Jieqing Chen,Yun Wu,Zixing Liu

doi:10.1074/jbc.m112.422071

Abstract

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.

Highlights

These findings strongly argue that combining chemotherapeutic agents with autophagy inhibition by repressing Heat shock factor 1 (HSF1)/ATG7 luciferase vector (ATG7) axis represents a promising strategy for future cancer treatment
Using stable HSF1-knockdown cells, we identified that binding of HSF1 was required to increase the H3 acetylation at the ATG7 promoter region
Because higher acetylation status of the ATG7 promoter region is associated with increased ATG7 expression [39], our data suggest that the absence of HSF1 at the ATG7 promoter prevented H3 acetylation, leading to repression of ATG7 and formation of autophagosomes leading to increased chemosensitivity

Summary

Background

In this study we demonstrated that HSF1 is required for chemotherapeutic agent-induced cytoprotective autophagy through transcriptional up-regulation of autophagy-related gene ATG7 This is independent of the HSF1 heat shock response function. This report shows that in cancer cells, HSF1 is required for chemotherapy-induced cytoprotective autophagy, and this is independent of HSF1 function in heat shock response This is the first study to demonstrate that HSF1, a multifunctional transcription factor, is activated by carboplatin treatment and leads to up-regulation of a novel HSF1 target gene ATG7. This regulation plays a critical role in cancer cell resistance to chemotherapy

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION