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RCCD1 promotes breast carcinogenesis through regulating hypoxia-associated mitochondrial homeostasis

Oncogene volume 42, pages 3684–3697 (2023)Cite this article

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Abstract

Regulator of chromosome condensation domain-containing protein 1 (RCCD1), previously reported as a partner of histone H3K36 demethylase KDM8 involved in chromosome segregation, has been identified as a potential driver for breast cancer in a recent transcriptome-wide association study. We report here that, unexpectedly, RCCD1 is also localized in mitochondria. We show that RCCD1 resides in the mitochondrial matrix, where it interacts with the mitochondrial contact site/cristae organizing system (MICOS) and mitochondrial DNA (mtDNA) to regulate mtDNA transcription, oxidative phosphorylation, and the production of reactive oxygen species. Interestingly, RCCD1 is upregulated under hypoxic conditions, leading to decreased generation of reactive oxygen species and alleviated apoptosis favoring cancer cell survival. We show that RCCD1 promotes breast cancer cell proliferation in vitro and accelerates breast tumor growth in vivo. Indeed, RCCD1 is overexpressed in breast carcinomas, and its level of expression is associated with aggressive breast cancer phenotypes and poor patient survival. Our study reveals an additional dimension of RCCD1 functionality in regulating mitochondrial homeostasis, whose dysregulation inflicts pathologic states such as breast cancer.

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Fig. 1: RCCD1 Is Localized in Mitochondrial Matrix and Interacts with the MICOS Complex.
Fig. 2: RCCD1 Directly Binds to mtDNA in a Sequence-independent Manner.
Fig. 3: RCCD1 Suppresses mtDNA Transcription to Downregulate mtDNA-encoded Oxidative Phosphorylation Enzymes.
Fig. 4: RCCD1 Regulates Mitochondrial Bioenergetics and ROS Production.
Fig. 5: RCCD1 Is Upregulated under Hypoxia by HIF1α.
Fig. 6: RCCD1 Inhibits Cell Apoptosis under Normoxia and Hypoxia.
Fig. 7: Overexpression of RCCD1 Promotes Breast Carcinogenesis in vivo.

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Data availability

RNA-seq data are available in the GEO database under accession number GSE219134.

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Acknowledgements

This work was supported by grants (2021YFA1300603 to YS and 2019YFA0508904 to JL) from the Ministry of Science and Technology of China, and grants (82188102 and 31991164 to YS and 82273155 to JL) from the National Natural Science Foundation of China.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China

    Yani Peng, Xiaoping Liu, Xiao Cheng, Lu Xia, Leyi Qin, Sudun Guan, Yue Wang, Yu Zhang, Luyang Sun, Jing Liang & Yongfeng Shang

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, 311121, Hangzhou, China

    Xinhua Liu, Yue Wang & Yongfeng Shang

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, China

    Xiaodi Wu, Jiajing Wu, Dong Yan & Yongfeng Shang

  4. Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China

    Jianying Liu

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Contributions

YP, JL, and YS conceived the project, designed experiments, analyzed data and wrote the paper. YP, XL, XC, Lu X, LQ, SG, YW, XW, JW, DY, YZ, LS performed experiments and analyzed data. Xinhua L performed bioinformatics analysis. Jianying L instructed pathological analysis. All authors reviewed the paper.

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Correspondence to Jing Liang or Yongfeng Shang.

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All studies were approved by the Ethics Committee of Peking University Health Science Center. Animal handling and procedures were approved by Peking University Health Science Center Institutional Animal Care and Use Committee.

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Peng, Y., Liu, X., Liu, X. et al. RCCD1 promotes breast carcinogenesis through regulating hypoxia-associated mitochondrial homeostasis. Oncogene 42, 3684–3697 (2023). https://doi.org/10.1038/s41388-023-02877-2

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