2. Academic Validation
  3. USP19 exacerbates lipogenesis and colorectal carcinogenesis by stabilizing ME1

USP19 exacerbates lipogenesis and colorectal carcinogenesis by stabilizing ME1

  • Cell Rep. 2021 Dec 28;37(13):110174. doi: 10.1016/j.celrep.2021.110174.
Yahui Zhu 1,  Li Gu 2,  Xi Lin 2,  Xinyi Zhou 2,  Bingjun Lu 2,  Cheng Liu 2,  Caoqi Lei 3,  Feng Zhou 4,  Qiu Zhao 4,  Edward V Prochownik 5,  Youjun Li 6
Affiliations

Affiliations

  • 1 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China; Medical Research Institute, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
  • 2 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China; Medical Research Institute, Wuhan University, Wuhan 430071, China.
  • 3 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 4 Department of Gastroenterology, Zhongnan Hospital of Wuhan University School of Medicine, Wuhan 430071, China; Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal Diseases, Wuhan 430071, China.
  • 5 Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, The Department of Microbiology and Molecular Genetics, The Pittsburgh Liver Research Center and The Hillman Cancer Center of UPMC, The University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
  • 6 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China; Medical Research Institute, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
PMID: 34965422 DOI: 10.1016/j.celrep.2021.110174
Abstract

Lipogenesis plays a critical role in colorectal carcinogenesis, but precisely how remains unclear. Here, we show that ERK2 phosphorylates ME1 at T103, thereby inhibiting its polyubiquitination and proteasomal degradation and enhancing its interaction with USP19. USP19 antagonizes RNF1-mediated ME1 degradation by deubiquitination, which in turn promotes lipid metabolism and NADPH production and suppresses ROS. Meanwhile, ROS dramatically increases PD-L1 mRNA levels through accelerating expression of the transcription factor NRF2. Increased lipid metabolism is correlated with ERK2 activity and colorectal carcinogenesis in human patients. Therefore, the combination of ERK2 Inhibitor and anti-PD-L1 antibody significantly inhibits spontaneous and chemically induced colorectal carcinogenesis. Collectively, the USP19-ME1 axis plays a vital role in colorectal carcinogenesis and may also provide a potential therapeutic target.

Keywords

ME1; PD-L1; USP19; deubiquitination; lipogenesis.

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