2. Academic Validation
  3. UTP11 deficiency suppresses cancer development via nucleolar stress and ferroptosis

UTP11 deficiency suppresses cancer development via nucleolar stress and ferroptosis

  • Redox Biol. 2023 Jun:62:102705. doi: 10.1016/j.redox.2023.102705.
Yu Gan 1,  Jun Deng 2,  Qian Hao 3,  Yingdan Huang 3,  Tao Han 4,  Jin-Guo Xu 4,  Min Zhao 5,  Litong Yao 6,  Yingying Xu 6,  Jianping Xiong 2,  Hua Lu 7,  Chunmeng Wang 8,  Jiaxiang Chen 9,  Xiang Zhou 10
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China; Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
  • 2 Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
  • 3 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 4 Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, 453003, China.
  • 5 School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore DC, Queensland, 4558, Australia.
  • 6 Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
  • 7 Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
  • 8 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. Electronic address: [email protected].
  • 9 Department of Physiology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China. Electronic address: [email protected].
  • 10 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
PMID: 37087976 DOI: 10.1016/j.redox.2023.102705
Abstract

The eukaryotic ribosome is essential for Cancer cell survival. Perturbation of ribosome biogenesis induces nucleolar stress or ribosomal stress, which restrains Cancer growth, as rapidly proliferating Cancer cells need more active ribosome biogenesis. In this study, we found that UTP11 plays an important role in the biosynthesis of 18S ribosomal RNAs (rRNA) by binding to the pre-rRNA processing factor, MPP10. UTP11 is overexpressed in human cancers and associated with poor prognoses. Interestingly, depletion of UTP11 inhibits Cancer cell growth in vitro and in vivo through p53-depedednt and -independent mechanisms, whereas UTP11 overexpression promotes Cancer cell growth and progression. On the one hand, the ablation of UTP11 impedes 18S rRNA biosynthesis to trigger nucleolar stress, thereby preventing MDM2-mediated p53 ubiquitination and degradation through ribosomal proteins, RPL5 and RPL11. On the Other hand, UTP11 deficiency represses the expression of SLC7A11 by promoting the decay of NRF2 mRNA, resulting in reduced levels of glutathione (GSH) and enhanced Ferroptosis. Altogether, our study uncovers a critical role for UTP11 in maintaining Cancer cell survival and growth, as depleting UTP11 leads to p53-dependent Cancer cell growth arrest and p53-independent Ferroptosis.

Keywords

Ferroptosis; Nucleolar stress; Ribosome biogenesis; SLC7A11; UTP11; p53.

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