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A mitochondrial outer membrane protein TOMM20 maintains protein stability of androgen receptor and regulates AR transcriptional activity in prostate cancer cells

Oncogene volume 44, pages 1567–1577 (2025)Cite this article

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Abstract

Prostate cancer (PCa) is an androgen-dependent malignancy, with HSP90 and HSP70 serving as classical molecular chaperones that maintain androgen receptor (AR) protein stability and regulate its transcriptional activation. Surprisingly, our study identified TOMM20, a mitochondrial outer membrane protein, as a potential molecular chaperone with similar roles to HSP90/HSP70. We found that TOMM20 expression is elevated in PCa tissues and cell lines and positively correlates with AR levels. RNA-seq analysis revealed that TOMM20 knockdown significantly reduced the mRNA levels of AR-regulated genes. Additionally, the protein level of KLK3 (PSA) decreased, and AR binding to the androgen response element (ARE) of the KLK3 promoter was diminished following TOMM20 knockdown, leading to decreased KLK3 gene transcription. Furthermore, TOMM20 depletion reduced both cytoplasmic and nuclear AR protein levels and facilitated AR degradation via an E3 ubiquitin ligase SKP2-mediated ubiquitin-proteasome pathway, independent of heat shock proteins (HSPs). To our knowledge, this is the first report demonstrating that TOMM20, a mitochondrial outer translocase protein, stabilizes AR protein and enhances its transcriptional activity, while its knockdown promotes AR degradation through the SKP2-mediated ubiquitin-proteasome pathway. These findings suggest that TOMM20 may serve as a potential biomarker for PCa progression and a promising therapeutic target for drug development.

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Fig. 1: TOMM20 is overexpressed in prostate cancer (PCa) cells and tumor specimens.
Fig. 2: TOMM20 regulates AR regulatory genes.
Fig. 3: TOMM20 promotes AR-regulated KLK3 gene transcription.
Fig. 4: TOMM20 mantains AR protein stability, while TOMM20 knockdown promotes SKP2-mediated ubiquitination degradation of AR protein.
Fig. 5: TOMM20 knockdown decreased the levels of nuclear and cytoplasmic AR protein of prostate cancer cells.
Fig. 6: TOMM20 regulates AR regulatory genes through the mechanisms independent of HSP proteins.
Fig. 7: Schematic representation of mechanism of TOMM20 in the regulation of AR signaling pathway.

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Data availability

The RNA-seq data in this manuscript have been submitted to the National Centre for Biotechnology (BioProject ID:PRJAN783133). The public datasets used in this study were downloaded from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/) and the cBioPortal(http://www.cbioportal.org/). All relevant data are available from the corresponding authors upon reasonable request.

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Funding

This study was funded by the National Natural Science Foundation of China (NSFC 81572542, NSFC 81874096), Research Project of Key Discipline of Guangdong Province (2019GDXK0010), Science and Technology Program of Guangzhou City (202102021130), National Key Specialty Construction Project of Clinical Pharmacy, High Level Clinical Key Specialty of Clinical Pharmacy in Guangdong Province, and Key Engineering Team, Discipline Cultvation Projects, Guangdong Pharmaceutical University (2024ZZ10).

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Authors and Affiliations

  1. Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, China

    Linglong Yin, Yi Dai, Yue Wang, Shiwen Liu, Yubing Ye, Yongming Fu, Yuchong Peng, Li Fang, Haoran Suo & Xiong Li

  2. Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, 510699, China

    Linglong Yin, Yi Dai, Yue Wang, Shiwen Liu, Yubing Ye, Yongming Fu, Yuchong Peng, Li Fang, Haoran Suo & Xiong Li

  3. NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Linglong Yin, Yi Dai, Yue Wang, Shiwen Liu, Yubing Ye, Yongming Fu, Yuchong Peng, Li Fang, Haoran Suo & Xiong Li

  4. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Linglong Yin, Yi Dai, Yue Wang, Shiwen Liu, Li Fang & Haoran Suo

  5. BaiSheng (GuangZhou) Biological Products Co. Ltd., Guangzhou, China

    Ruizheng Tan

  6. School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China

    Xuli Qi & Xiong Li

  7. Department of Pathology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Bowen Yuan

  8. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Yingxue Gao

  9. Xiangya Cancer Center, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China

    Youhong Liu

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  1. Linglong Yin
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Contributions

YLL:data collection and analysis, project development. DY:data collection and project development. WY, LSW, YYB, FYM, PYC, TRZ, FL, SHR, QXL, YBW, GYX, LYH: data collection and analysis. YLL and LX: manuscript writing. LX: idea development, data management and analysis and manuscript writing. All authors read and approved the final manuscript.

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Correspondence to Xiong Li.

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Yin, L., Dai, Y., Wang, Y. et al. A mitochondrial outer membrane protein TOMM20 maintains protein stability of androgen receptor and regulates AR transcriptional activity in prostate cancer cells. Oncogene 44, 1567–1577 (2025). https://doi.org/10.1038/s41388-025-03328-w

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