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CHIP induces ubiquitination and degradation of HMGB1 to regulate glycolysis in ovarian endometriosis

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A Correction to this article was published on 17 March 2023

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Abstract

Ovarian endometriosis is a common gynecological condition that can cause infertility in women of childbearing age. However, the pathogenesis is still unknown. We demonstrate that the carboxyl terminus of Hsc70-interacting protein (CHIP) is a negative regulator in the development of endometriosis and reduces HMGB1 expression in endometriotic cells. Meanwhile, CHIP interacts with HMGB1 and promotes its ubiquitinated degradation, thereby inhibiting aerobic glycolysis and the progression of endometriosis. Furthermore, the CHIP agonist YL-109 effectively suppresses the growth of ectopic endometrium in endometriosis mouse model, which could be a potential therapeutic approach for endometriosis. In conclusion, our data suggest that CHIP may inhibit the development of endometriosis by suppressing the HMGB1-related glycolysis.

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Acknowledgements

We thank Prof. Sun-wei Guo (Fudan University, Shanghai) for generously providing the cell line.

Funding

This research was supported by the National Natural Science Foundation of China (nos. 81602301 and 81972489), Natural Science Foundation of Shandong Province (no. ZR2021MH235), Shandong Province College Science and Technology Plan Project (no. J17KA254), and Clinical Research Center of Affiliated Hospital of Weifang Medical University (no. 2021wyfylcyj01).

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  1. Yujun Sun, Qian Wang, and Mengxue Wang have contributed equally.

Authors and Affiliations

  1. Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of China

    Yujun Sun, Qian Wang, Mengxue Wang, Fangyuan Sun, Pengyun Qiao, Aifang Jiang, Chune Ren, Zhenhai Yu & Tingting Yang

  2. School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, People’s Republic of China

    Yujun Sun, Qian Wang, Mengxue Wang & Fangyuan Sun

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Contributions

TY, ZY, YS, and QW designed the study; YS, MW, and FS performed the experiments; PQ and AJ reviewed the data and advised the study; CR, ZY, and TY supervised the study; YS and QW wrote the manuscript.

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Correspondence to Chune Ren, Zhenhai Yu or Tingting Yang.

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18_2022_4637_MOESM1_ESM.tif

Supplementary Fig. 1. CHIP suppresses cell proliferation and invasion in vitro. A-B Immunoblot analysis revealed overexpression and knockdown levels of CHIP in EESC cell. Western blot was quantified by Image J software and statistics were normalized to β-actin. C-D Effect of CHIP overexpression or knockdown on the proliferation of EESC cells. E Overexpression of CHIP in EESC cells resulted in a significant decrease of colony formation. Knockdown of CHIP in EESC cells resulted in a significant increase of colony formation. F Overexpression of CHIP in EESC cells resulted in diminished cell invasion. Knockdown of CHIP in EESC cells resulted in enhanced cell invasion. G CHIP overexpression suppressed endometriotic cells migration. CHIP knockdown enhanced endometriotic cells migration. H-I The effects on glucose consumption and lactate production after overexpression or knockdown of CHIP are indicated, respectively. (All data represent mean ± SEM. The Student’s t-test was used for data analysis. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.) (TIF 4192 KB)

18_2022_4637_MOESM2_ESM.tif

Supplementary Fig. 2. Co-localization of CHIP and HMGB1 in cells and tissues. A Representative images of in situ PLA showing the interaction between CHIP and HMGB1 in 11Z cells (scale bar, 20 µm). B Confocal immunofluorescence microscopy was performed to analyze localization of CHIP (red) and HMGB1 (green) in human and mouse ectopic endometrium (scale bar, 20 µm). (TIF 3589 KB)

18_2022_4637_MOESM3_ESM.tif

Supplementary Fig. 3. CHIP decreases the protein level of HMGB1. A-B 11Z or EESC cells were treated with YL-109 (10μmo/L). Immunoblotting experiments were performed. C 11Z cells with overexpression of Flag-CHIP were treated with CHX for indicated time. Immunoblotting experiments were performed. D 11Z cells with knockdown of CHIP were treated with CHX for indicated time. Immunoblotting experiments were performed. (Representative western blot was quantified by Image J software and statistics were normalized to β-actin. All data represent mean ± SEM. Statistical significance was analyzed with Student’s t-test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.) (TIF 1174 KB)

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Sun, Y., Wang, Q., Wang, M. et al. CHIP induces ubiquitination and degradation of HMGB1 to regulate glycolysis in ovarian endometriosis. Cell. Mol. Life Sci. 80, 13 (2023). https://doi.org/10.1007/s00018-022-04637-z

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