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USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer

Author

Listed:
  • Dongni Shi

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine)

  • Xianqiu Wu

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
    Southern Medical University)

  • Yunting Jian

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
    The Third Affiliated Hospital of Guangzhou Medical University)

  • Junye Wang

    (Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine)

  • Chengmei Huang

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
    Southern Medical University)

  • Shuang Mo

    (Sun Yat-sen University)

  • Yue Li

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine)

  • Fengtian Li

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine)

  • Chao Zhang

    (Sun Yat-sen University Cancer Center)

  • Dongsheng Zhang

    (Sun Yat-sen University Cancer Center)

  • Huizhong Zhang

    (Sun Yat-sen University Cancer Center)

  • Huilin Huang

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine)

  • Xin Chen

    (Guangzhou Medical University)

  • Y. Alan Wang

    (Indiana University School of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center)

  • Chuyong Lin

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine)

  • Guozhen Liu

    (The Chinese University of Hong Kong)

  • Libing Song

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
    Guangzhou Medical University)

  • Wenting Liao

    (Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine)

Abstract

Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy.

Suggested Citation

  • Dongni Shi & Xianqiu Wu & Yunting Jian & Junye Wang & Chengmei Huang & Shuang Mo & Yue Li & Fengtian Li & Chao Zhang & Dongsheng Zhang & Huizhong Zhang & Huilin Huang & Xin Chen & Y. Alan Wang & Chuyo, 2022. "USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33285-x
    DOI: 10.1038/s41467-022-33285-x
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    References listed on IDEAS

    as
    1. George C. Prendergast, 2011. "Why tumours eat tryptophan," Nature, Nature, vol. 478(7368), pages 192-194, October.
    2. Byung-Hoon Lee & Ying Lu & Miguel A. Prado & Yuan Shi & Geng Tian & Shuangwu Sun & Suzanne Elsasser & Steven P. Gygi & Randall W. King & Daniel Finley, 2016. "USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites," Nature, Nature, vol. 532(7599), pages 398-401, April.
    3. Bin Liu & Shangwen Jiang & Min Li & Xuelian Xiong & Mingrui Zhu & Duanzhuo Li & Lei Zhao & Lili Qian & Linhui Zhai & Jing Li & Han Lu & Shengnan Sun & Jiandie Lin & Yan Lu & Xiaoying Li & Minjia Tan, 2018. "Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    4. Alban Bessede & Marco Gargaro & Maria T. Pallotta & Davide Matino & Giuseppe Servillo & Cinzia Brunacci & Silvio Bicciato & Emilia M. C. Mazza & Antonio Macchiarulo & Carmine Vacca & Rossana Iannitti , 2014. "Aryl hydrocarbon receptor control of a disease tolerance defence pathway," Nature, Nature, vol. 511(7508), pages 184-190, July.
    5. Byung-Hoon Lee & Min Jae Lee & Soyeon Park & Dong-Chan Oh & Suzanne Elsasser & Ping-Chung Chen & Carlos Gartner & Nevena Dimova & John Hanna & Steven P. Gygi & Scott M. Wilson & Randall W. King & Dani, 2010. "Enhancement of proteasome activity by a small-molecule inhibitor of USP14," Nature, Nature, vol. 467(7312), pages 179-184, September.
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