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  3. The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth

The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth

  • Cell Discov. 2023 Jul 25;9(1):76. doi: 10.1038/s41421-023-00558-8.
Xiaojun Ren # 1 2 3,  Jimei Yan # 3,  Qiongya Zhao 1,  Xinzhu Bao 3,  Xinyu Han 3,  Chen Zheng 3,  Yan Zhou 3,  Lifang Chen 3,  Bo Wang 3,  Lina Yang 3,  Xi Lin 3,  Dandan Liu 3,  Yuyan Lin 3,  Min Li 4 5,  Hezhi Fang 6,  Zhimin Lu 7 8,  Jianxin Lyu 9 10
Affiliations

Affiliations

  • 1 School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2 Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 3 Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 5 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
  • 6 Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. fangh@wmu.edu.cn.
  • 7 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. zhiminlu@zju.edu.cn.
  • 8 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China. zhiminlu@zju.edu.cn.
  • 9 School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China. jxlu313@163.com.
  • 10 Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China. jxlu313@163.com.
  • # Contributed equally.
PMID: 37488138 DOI: 10.1038/s41421-023-00558-8
Abstract

IscU2 is a scaffold protein that is critical for the assembly of iron-sulfur (Fe-S) clusters and the functions of Fe-S-containing mitochondrial proteins. However, the role of IscU2 in tumor development remains unclear. Here, we demonstrated that IscU2 expression is much higher in human pancreatic ductal adenocarcinoma (PDAC) tissues than in adjacent normal pancreatic tissues. In PDAC cells, activated KRAS enhances the c-Myc-mediated IscU2 transcription. The upregulated IscU2 stabilizes Fe-S cluster and regulates the activity of tricarboxylic acid (TCA) cycle Enzymes α-ketoglutarate (α-KG) dehydrogenase and aconitase 2, which promote α-KG catabolism through oxidative and reductive TCA cycling, respectively. In addition to promoting mitochondrial functions, activated KRAS-induced and IscU2-dependent acceleration of α-KG catabolism results in reduced α-KG levels in the cytosol and nucleus, leading to an increase in DNA 5mC due to Tet methylcytosine dioxygenase 3 (TET3) inhibition and subsequent expression of genes including DNA Polymerase alpha 1 catalytic subunit for PDAC cell proliferation and tumor growth in mice. These findings underscore a critical role of IscU2 in KRAS-promoted α-KG catabolism, 5mC-dependent gene expression, and PDAC growth and highlight the instrumental and integrated regulation of mitochondrial functions and gene expression by IscU2 in PDAC cells.

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