HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells
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Updated: Feb 23, 2026
Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells
Published on: June 30, 2023
Nan Zhang1, Yaran Wu1, Xilin Lyu1
1Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
Abstract:
Considerable evidences have shown that both heat shock transcription factor 1 (HSF1) and autophagy can attenuate the sensitivity of hepatocellular carcinoma (HCC) cells to chemotherapeutic reagents. However, it is still little known whether HSF1 is associated with autophagy in regulating the chemosensitivity of HCC cells. In this study, we for the first time demonstrated that HSF1 markedly attenuated the killing effect of epirubicin (EPI) to HCC cells via enhancing the EPI-induced protective autophagy. Mechanistically, HSF1 upregulated autophagy related 4B (ATG4B) in HCC cells, which enhanced the EPI-triggered protective autophagy. Reporter assay showed that HSF1 increased the transcriptional activity of ATG4B gene promoter, and chromatin immunoprecipitation assay verified that HSF1 bound to the site (-1429 to -1417) in ATG4B gene promoter region. The experiments in nude mice showed that knockdown of HSF1 or ATG4B strengthened the anti-HCC effect of EPI in vivo. Collectively, these results revealed that HSF1 elevates ATG4B via promoting its transcription, which alleviates the sensitivity of EPI in HCC cells through enhancing protective autophagy, suggesting that the "HSF1/ATG4B/protective autophagy" pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy.
Insights
Heat shock transcription factor 1 (HSF1) enhances protective autophagy in hepatocellular carcinoma (HCC) cells, reducing sensitivity to epirubicin (EPI) chemotherapy by upregulating ATG4B. Targeting the HSF1/ATG4B pathway could improve HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Heat shock transcription factor 1 (HSF1) and autophagy are known to reduce hepatocellular carcinoma (HCC) cell sensitivity to chemotherapy.
- The interplay between HSF1 and autophagy in regulating HCC chemosensitivity remains largely unexplored.
Purpose of the Study:
- To investigate the association between HSF1 and autophagy in modulating the chemosensitivity of HCC cells.
- To elucidate the underlying molecular mechanisms by which HSF1 influences HCC cell response to epirubicin (EPI).
Main Methods:
- Utilized reporter assays to assess HSF1's effect on ATG4B gene promoter activity.
- Performed chromatin immunoprecipitation (ChIP) assays to confirm HSF1 binding to the ATG4B promoter.
- Conducted in vivo experiments using nude mice to evaluate the therapeutic effects of targeting HSF1 and ATG4B.
Main Results:
- HSF1 was found to attenuate the cytotoxic effects of EPI on HCC cells by enhancing EPI-induced protective autophagy.
- HSF1 upregulates autophagy related 4B (ATG4B) expression, thereby promoting protective autophagy.
- HSF1 directly binds to and increases the transcriptional activity of the ATG4B gene promoter.
- Knockdown of HSF1 or ATG4B significantly enhanced the anti-HCC efficacy of EPI in vivo.
Conclusions:
- HSF1 promotes HCC cell survival during EPI treatment by upregulating ATG4B transcription and enhancing protective autophagy.
- The identified HSF1/ATG4B/protective autophagy pathway represents a potential therapeutic target for overcoming chemoresistance in HCC.
- Targeting this pathway may offer a novel strategy to sensitize HCC to existing chemotherapeutic agents.
