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Cancer progression is mediated by proline catabolism in non-small cell lung cancer

Oncogene volume 39, pages 2358–2376 (2020)Cite this article

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Abstract

Dysregulated metabolism contributes to cancer initiation and progression, but the key drivers of these pathways are just being discovered. Here, we report a critical role for proline catabolism in non-small cell lung cancer (NSCLC). Proline dehydrogenase (PRODH) is activated to reduce proline levels by the chromatin remodeling factor lymphoid-specific helicase (LSH), an epigenetic driver of NSCLC. PRODH promotes NSCLC tumorigenesis by inducing epithelial to mesenchymal transition (EMT) and IKKα-dependent inflammatory genes, including CXCL1, LCN2, and IL17C. Consistently, proline addition promotes the expression of these inflammatory genes, as well as EMT, tumor cell proliferation, and migration in vitro and tumor growth in vivo, while the depletion or inhibition of PRODH blocks these phenotypes. In summary, we reveal an essential metabolic pathway amenable to targeting in NSCLC.

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Fig. 1: LSH decreases levels of proline in NSCLC.
Fig. 2: LSH regulates PRODH expression in a p53-dependent manner.
Fig. 3: Overexpression of PRODH promotes NSCLC progression.
Fig. 4: Depletion of PRODH attenuates NSCLC progression.
Fig. 5: PRODH regulates Cxcl1, Lcn2, and IL17c inflammatory genes.
Fig. 6: PRODH regulates inflammatory cytokines by affecting phosphorylation of IKKα.
Fig. 7: Proline catabolism via PRODH supports NSCLC progression.

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Acknowledgements

We thank Prof. Dangsheng Li (Deputy Editor-in-Chief, Cell Research, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China) and Prof. Teibang Kang (State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng East Road, Guangzhou, 510060, China) very much for the kind suggestions.,

Funding

This work was supported by the National Natural Science Foundation of China [81872285 (YS), 81728014 (YT), 81672787 (YT), 81672991, and 81874139 (SL), 81672308 (XW), 81772496 (DX)]; the National Basic Research Program of China [2015CB553903 (YT)], the Overseas Expertize Introduction Project for Discipline Innovation (111 Project, No. 111-2-12), Hunan Provincial Key Area R&D Programs [2019SK2253 (XW)], the Fundamental Research Funds for the Central Universities [1502211723 (YL)], and Open projects of Key Laboratory of Carcinogenesis and Invasion, Ministry of Education (Central South University) [201805, (CC and YT)].

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  1. Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China

    Yating Liu, Chao Mao, Min Wang, Na Liu, Lianlian Ouyang, Shouping Liu, Haosheng Tang, Ya Cao, Ying Shi & Yongguang Tao

  2. NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China

    Yating Liu, Chao Mao, Min Wang, Na Liu, Lianlian Ouyang, Shouping Liu, Haosheng Tang, Ying Shi & Yongguang Tao

  3. Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Shuang Liu

  4. Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Xiang Wang & Yongguang Tao

  5. Department of Pathology, School of Basic Medicine and Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Desheng Xiao

  6. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan, 650223, China

    Ceshi Chen

  7. Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA

    Qin Yan

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Contributions

YT, YS, QY, and SL designed/planned the study and wrote the paper. YL performed experiments using the three types of cells and analyzed data. YL performed MS measurements and analyzed data. CM, MW, and NL participated in writing the paper. OY and MW performed imaging analysis. OY and YL performed in vitro biochemical experiments. DX, XW, CC, YC, and YT participated in discussion of related experiments. SL, HT, and NL performed computational modeling. XD and XW acquired and analyzed clinical and experimental data. MW, YL, and OY performed experiments and analyzed data.

Corresponding authors

Correspondence to Ying Shi, Qin Yan or Yongguang Tao.

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Liu, Y., Mao, C., Wang, M. et al. Cancer progression is mediated by proline catabolism in non-small cell lung cancer. Oncogene 39, 2358–2376 (2020). https://doi.org/10.1038/s41388-019-1151-5

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