IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia

Ke Zheng, Nannan Sha, Guofang Hou, Zhuyun Leng, Qin Zhao, Li Zhang, Lingnan He, Meidong Xu (), Yuhui Jiang () and Tao Chen ()
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Ke Zheng: The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital
Nannan Sha: Shanghai Jiao Tong University School of Medicine
Guofang Hou: Shanghai Jiao Tong University School of Medicine
Zhuyun Leng: Tongji University
Qin Zhao: Shanghai Jiao Tong University School of Medicine
Li Zhang: Tongji University
Lingnan He: Tongji University
Meidong Xu: Tongji University
Yuhui Jiang: Shanghai Jiao Tong University School of Medicine
Tao Chen: Tongji University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The proline synthesis is importantly involved in tumor growth under hypoxia, while the underlying mechanism remains to be further investigated. Here we show that pyrroline-5-carpoxylate reductase-1 (PYCR1), displaying a constant nuclear localization, is phosphorylated by nuclear IGF1R at Tyrosine 135 under hypoxia; this phosphorylation promotes the binding of PYCR1 to ELK4 and thus PYCR1 recruitment to ELK4-targeted genes promoter. Under hypoxia, ELK4-binding ability and enzymatic activity of PYCR1 are both required for ELK4-Sirt7-mediated transcriptional repression and cell growth maintenance, in which PYCR1-catalyzed NAD+ production stimulates the deacetylation activity of Sirt7 on H3K18ac that restrains genes transcription. Functionally, PYCR1 Tyr-135 phosphorylation exerts supportive effect on tumor growth under hypoxia, and the level of PYCR1 Tyr-135 phosphorylation is associated with malignancy of colorectal cancer (CRC). These data uncover the relationship between the compartmentally metabolic activity of PYCR1 and genes transcription regulation, and highlight the oncogenic role of PYCR1 during CRC development.

Date: 2023
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DOI: 10.1038/s41467-023-41658-z

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