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Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression

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Abstract

Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.

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All data and material during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (Grants No. 82172818, 81972416), (Grant No. 81772760, 82072850), (Grant No. 81972436), Joint Research Fund of Natural Science of Shandong Province (ZR2019LZL014), Academic promotion program of Shandong First Medical University (LJ001), The Youth Innovation Technology Plan of Shandong University (Grant No. 2019KJK003), China Postdoctoral Science Foundation (2022M711900) and Natural Science Foundation of Shandong Province (ZR202111150013).

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Author notes

  1. Tingting Feng, and Ru Zhao have Contributed equally to this work.

Authors and Affiliations

  1. The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China

    Tingting Feng, Ru Zhao, Hanwen Zhang, Feifei Sun, Meng Wang, Lin Gao, Junhui Zhen & Bo Han

  2. Department of Pathology, Qilu Hospital, Shandong University, Jinan, Shandong, China

    Ru Zhao, Jing Hu, Mei Qi, Ling Liu, Junhui Zhen & Bo Han

  3. School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China

    Yabo Xiao

  4. Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China

    Weiwen Chen

  5. Biomedical Sciences College and Shandong Medicinal Biotechnology Centre, NHC Key Laboratory of Biotechnology Drugs, Key Lab for Rare and Uncommon Diseases of Shandong Province, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Lin Wang

  6. Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China

    Lin Wang

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  1. Tingting Feng
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Contributions

BH, LW, TF, and RZ wrote the manuscript, performed, designed, and analyzed experiments; FS, HZ, and LG accomplished some of in vitro experiments; WC and MW analyzed experiments; TF, and YX accomplished some of in vivo studies; JH, MQ, JZ and LL analyzed IHC assay. All authors read and approved the final manuscript.

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Correspondence to Lin Wang or Bo Han.

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The authors declare no competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Shandong University (Document No. ECSBMSSDU2021-1-61). All animal experimental protocols were performed following the Ethical Animal Care and Use Committee of Shandong University (Document No. ECSBMSSDU2021-2-126).

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Feng, T., Zhao, R., Zhang, H. et al. Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression. Cell. Mol. Life Sci. 80, 292 (2023). https://doi.org/10.1007/s00018-023-04940-3

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