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Int J Biol Sci 2024; 20(6):2130-2148. doi:10.7150/ijbs.94058 This issue Cite

Research Paper

Dysregulated Ribosome Biogenesis Is a Targetable Vulnerability in Triple-Negative Breast Cancer: MRPS27 as a Key Mediator of the Stemness-inhibitory Effect of Lovastatin

Chanjuan Zheng^1,2, Hui Yao^1,2, Lu Lu^1,2, Hongqi Li³, Lei Zhou³, Xueyan He³, Xi Xu^1,2, Hongzhuo Xia^1,2, Siyu Ding^1,2, Yiyuan Yang^1,2, Xinyu Wang^1,2, Muyao Wu^1,2, Lian Xue^1,2, Sisi Chen^1,2, Xiaojun Peng⁴, Zhongyi Cheng⁴, Yian Wang^1,2, Guangchun He^1,2, Shujun Fu^1,2, Evan T. Keller⁵, Suling Liu^3✉, Yi-zhou Jiang^6,7✉, Xiyun Deng^1,2✉

1. Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, Hunan, China.
2. Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China.
3. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
4. Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development Area, Hangzhou, China.
5. Department of Urology and Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
6. Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China.
7. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

✉ Corresponding authors: Xiyun Deng, Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan, China. E-mail: dengxiyunmededu.cn; Tel.: +86-731-88912415. Yi-Zhou Jiang, Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China. E-mail: yizhoujiangedu.cn; Tel.: +86-21-64438195. Suling Liu, Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China. E-mail: sulingedu.cn; Tel.: +86-21-34774409. More

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients.

Keywords: Triple-negative breast cancer, Ribosome biogenesis, Lovastatin, Stemness, MRPS27

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