Theranostics 2020; 10(8):3767-3778. doi:10.7150/thno.43142

Research Paper

PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation

Peifang Xu1,2,3*, Liping Jiang2*, Yang Yang4*, Mengge Wu2, Baiyang Liu2,3, Yulin Shi2,3, Qiushuo Shen2,4, Xiulin Jiang2,3, Yaomei He2,3, Dating Cheng5, Qiuxia Xiong5, Zuozhang Yang5, Lincan Duan5, Jie Lin5, Song Zhao4, Peng Shi6,7, Cuiping Yang2✉, Yongbin Chen2,7✉

1. School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
2. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
3. Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China.
4. Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
5. Kunming Medical University, Kunming 650223, China.
6. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
7. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
*These authors contributed equally to this work.

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Citation:
Xu P, Jiang L, Yang Y, Wu M, Liu B, Shi Y, Shen Q, Jiang X, He Y, Cheng D, Xiong Q, Yang Z, Duan L, Lin J, Zhao S, Shi P, Yang C, Chen Y. PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation. Theranostics 2020; 10(8):3767-3778. doi:10.7150/thno.43142. Available from https://www.thno.org/v10p3767.htm

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Abstract

Purpose: Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC).

Methods: The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4.

Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1.

Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.

Keywords: Progestin and AdipoQ Receptor 4, non-small cell lung cancer, Nrf2, Keap1, ubiquitination