2. Academic Validation
  3. Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis

Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis

  • EMBO J. 2025 Jan 28. doi: 10.1038/s44318-024-00359-z.
Yan Huang 1 2,  Hua Lu # 1 2,  Yao Liu # 3,  Jiabei Wang # 3,  Qingan Xia # 4,  Xiangmin Shi # 1 2,  Yan Jin 1 2,  Xiaolin Liang 1 2,  Wei Wang 1 2,  Xiaopeng Ma 5,  Yangyi Wang 5,  Meng Gong 1 2,  Canjun Li 5,  Chunlei Cang 5,  Qinghua Cui 6 7,  Ceshi Chen 8 9,  Tao Shen 10,  Lianxin Liu 11,  Xiangting Wang 12 13
Affiliations

Affiliations

  • 1 Department of Geriatrics, Gerontology Institute of Anhui Province, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2 Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, China.
  • 3 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 4 Department of Pathology, Tangshan Gongren Hospital, Tangshan, Hebei, China.
  • 5 Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 6 School of Sports Medicine, Wuhan Institute of Physical Education, Wuhan, Hubei, China.
  • 7 Department of Biomedical Informatics, Centre for Noncoding RNA Medicine, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 8 Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, Yunnan, China.
  • 9 Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China.
  • 10 Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Metabolic Diseases, Anhui Provincial Engineering Research Centre for Molecular Detection and Diagnostics, College of Life Sciences, Anhui Normal University, Wuhu, Anhui, China. stao@ahnu.edu.cn.
  • 11 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. Liulx@ustc.edu.cn.
  • 12 Department of Geriatrics, Gerontology Institute of Anhui Province, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. wangxt11@ustc.edu.cn.
  • 13 Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei, Anhui, China. wangxt11@ustc.edu.cn.
  • # Contributed equally.
PMID: 39875724 DOI: 10.1038/s44318-024-00359-z
Abstract

mTOR plays a pivotal role in Cancer growth control upon amino acid response. Recently, CDK Inhibitor P27KIP1 has been reported as a noncanonical inhibitor of mTOR signaling in MEFs, via unclear mechanisms. Here, we find that P27KIP1 degradation via E3 Ligase TRIM21 is inhibited by human micropeptide hSPAR through its C-terminus (hSPAR-C), causing P27KIP1's cytoplasmic accumulation in breast Cancer cells. Furthermore, hSPAR/hSPAR-C also serves as an inhibitor of glutamine transporter SLC38A2 expression and thereby decreases the cellular glutamine levels specifically in Cancer cells. The resultant glutamine deprivation sequentially triggers translocation of cytoplasmic P27KIP1 to lysosomes, where P27KIP1 disrupts the Ragulator complex and suppresses mTORC1 assembly. Administration of hSPAR or hSPAR-C significantly impedes breast Cancer cell proliferation and tumor growth in xenograft models. These findings define hSPAR as an intrinsic control factor for cellular glutamine levels and as a novel tumor suppressor inhibiting mTORC1 assembly.

Keywords

Breast Cancer; Micropeptide/microprotein; P27KIP1; TRIM21; mTOR.

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