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Heat shock protein family A member 8 serving as a co-activator of transcriptional factor ETV4 up-regulates PHLDA2 to promote the growth of liver cancer

Acta Pharmacologica Sinica volume 44, pages 2525–2536 (2023)Cite this article

Abstract

Heat shock protein family A member 8 (HSPA8) participates in the folding or degradation of misfolded proteins under stress and plays critical roles in cancer. In this study, we investigated the function of HSPA8 in the development of liver cancer. By analyzing the TCGA transcriptome dataset, we found that HSPA8 was upregulated in 134 clinical liver cancer tissue samples, and positively correlated with poor prognosis. IHC staining showed the nuclear and cytoplasmic localization of HSPA8 in liver cancer cells. Knockdown of HSPA8 resulted in a decrease in the proliferation of HepG2 and Huh-7 cells. ChIP-seq and RNA-seq analysis revealed that HSPA8 bound to the promoter of pleckstrin homology-like domain family A member 2 (PHLDA2) and regulated its expression. The transcription factor ETV4 in HepG2 cells activated PHLDA2 transcription. HSPA8 and ETV4 could interact with each other in the cells and colocalize in the nucleus. From a functional perspective, we demonstrated that HSPA8 upregulated PHDLA2 through the coactivating transcription factor ETV4 to enhance the growth of liver cancer in vitro and in vivo. From a therapeutic perspective, we identified both HSPA8 and PHDLA2 as novel targets in the treatment of HCC. In conclusion, this study demonstrates that HSPA8 serves as a coactivator of ETV4 and upregulates PHLDA2, leading to the growth of HCC, and is a potential therapeutic target in HCC treatment.

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Fig. 1: HSPA8 is overexpressed in HCC and positively correlates with poor prognosis.
Fig. 2: HSPA8 is able to promote the growth of liver cancer in vitro and in vivo.
Fig. 3: HSPA8 was identified to bind to the PHLDA2 promoter region.
Fig. 4: HSPA8 activates PHLDA2 transcription to enhance the growth of liver cancer in vitro and in vivo.
Fig. 5: HSPA8 coactivates the transcription factor ETV4 by binding to ETV4 in the promoter of PHLDA2 to upregulate PHLDA2.
Fig. 6: The HSPA8 mediated increase in PHLDA2 expression contributes to the growth of liver cancer in vitro and in vivo.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (No. 82103066) and the Natural Science Foundation of Tianjin Science and Technology Committee (19YFZCSY00020).

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  1. These authors contributed equally: Shuai Wang, Yu-fei Wang, Guang Yang

Authors and Affiliations

  1. Department of Hepatobiliary Oncology, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjinʼs Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, 300060, China

    Shuai Wang, Yu-hong Suo, Jiao Sun, Lin-lin Sun, Ning-ning Zhang & Wei Lu

  2. Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Tianjin Medical University Cancer Institute, and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China

    Yu-fei Wang, Guang Yang, Hui-hui Zhang, Hong-feng Yuan, Chun-yu Hou, Li-na Zhao, Pan Lv & Xiao-dong Zhang

  3. Department of Pathology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China

    Yan Sun

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Contributions

SW, YFW, and GY performed most of the experiments; HHZ, HFY, CYH, LNZ, YHS, JS, LLS, and PL accomplished some of the in vitro and in vivo experiments; XDZ, WL, NNZ, and YS conceived and designed the project and wrote the manuscript.

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Correspondence to Yan Sun, Ning-ning Zhang, Xiao-dong Zhang or Wei Lu.

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Wang, S., Wang, Yf., Yang, G. et al. Heat shock protein family A member 8 serving as a co-activator of transcriptional factor ETV4 up-regulates PHLDA2 to promote the growth of liver cancer. Acta Pharmacol Sin 44, 2525–2536 (2023). https://doi.org/10.1038/s41401-023-01133-3

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