Abstract
Cancer cells are defective in DNA repair, so they experience increased DNA strand breaks, genome instability, gene mutagenesis, and tumorigenicity; however, multiple classic DNA repair genes and pathways are strongly activated in malignant tumor cells to compensate for the DNA repair deficiency and gain an apoptosis resistance. The mechanisms underlying this phenomenon in cancer are unclear. We speculate that a key DNA repair gene or signaling pathway in cancer has not yet been recognized. Here, we show that the lipogenic liver X receptor (LXR)-sterol response element binding factor-1 (SREBF1) axis controls the transcription of a key DNA repair gene polynucleotide kinase/phosphatase (PNKP), thereby governing cancer cell DNA repair and apoptosis. Notably, the PNKP levels were significantly reduced in 95% of human pancreatic cancer (PC) patients, particularly deep reduction for sixfold in all of the advanced-stage PC cases. PNKP is also deficient in three other types of cancer that we examined. In addition, the expression of LXRs and SREBF1 was significantly reduced in the tumor tissues from human PC patients compared with the adjacent normal tissues. The newly identified LXR-SREBF1-PNKP signaling pathway is deficient in PC, and the defect in the pathway contributes to the DNA repair deficiency in the cancer. Strikingly, further diminution of the vulnerable LXR-SREBF1-PNKP signaling pathway using a small molecule triptonide, a new LXR antagonist identified in this investigation, at a concentration of 8 nM robustly activated tumor-suppressor p53 and readily elevated cancer cell DNA strand breaks over an apoptotic threshold, and selectively induced PC cell apoptosis, resulting in almost complete elimination of tumors in xenograft mice without obvious complications. Our findings provide new insight into DNA repair and apoptosis in cancer, and offer a new platform for developing novel anticancer therapeutics.
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06 April 2020
A Correction to this paper has been published: https://doi.org/10.1038/s41418-020-0534-z
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (grants no. 81372376, no. 81572257, no. 81703595, and no. 81772535); Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and the Chinese Ministry of Science and Technology; State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection; a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); Jiangsu Province’s Key Discipline of Medicine (XK201118); the 2011 Collaborative Innovation Center of Hematology of Jiangsu Province; Natural Science Funds of Jiangsu Colleges and Universities (No. 16KJB310015); and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases. We thank Dr. Jian Zhou, Bowen Chen, Jiaqi Zheng, and Mingcheng Guan for collecting cancer patient samples and data.
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Yang, B., Zhang, B., Cao, Z. et al. The lipogenic LXR-SREBF1 signaling pathway controls cancer cell DNA repair and apoptosis and is a vulnerable point of malignant tumors for cancer therapy. Cell Death Differ 27, 2433–2450 (2020). https://doi.org/10.1038/s41418-020-0514-3
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DOI: https://doi.org/10.1038/s41418-020-0514-3
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