2. Academic Validation
  3. STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth

STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth

  • J Biol Chem. 2024 May 6:107351. doi: 10.1016/j.jbc.2024.107351.
Yunzhou Fan 1,  Rui Zhang 2,  Chao Wang 2,  Meixia Pan 3,  Feng Geng 1,  Yaogang Zhong 1,  Huali Su 1,  Yongjun Kou 1,  Xiaokui Mo 4,  Etienne Lefai 5,  Xianlin Han 3,  Arnab Chakravarti 2,  Deliang Guo 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA.
  • 2 Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA.
  • 3 Barshop Institute for Longevity and Aging Studies, and Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 4 Biostatistic Center and Department of Bioinformatics, College of Medicine at The Ohio State University, Columbus, OH 43210, USA.
  • 5 Human Nutrition Unit, French National Research Institute for Agriculture, Food and Environment, University Clermont Auvergne, Clermont-Ferrand 63122, France.
  • 6 Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA. Electronic address: deliang.guo@osumc.edu.
PMID: 38718868 DOI: 10.1016/j.jbc.2024.107351
Abstract

SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human Cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple Cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and Phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.

Keywords

FASN; SCAP; SCD1; SREBP-1; STAT3; fatty acid; glioblastoma; lipogenesis; phospholipid.

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