ERα determines the chemo-resistant function of mutant p53 involving the switch between lincRNA-p21 and DDB2 expressions

Yu-Hao He; Ming-Hsin Yeh; Hsiao-Fan Chen; Tsu-Shing Wang; Ruey-Hong Wong; Ya-Ling Wei; Thanh Kieu Huynh; Dai-Wei Hu; Fang-Ju Cheng; Jhen-Yu Chen; Shu-Wei Hu; Chia-Chen Huang; Yeh Chen; Jiaxin Yu; Wei-Chung Cheng; Pei-Chun Shen; Liang-Chih Liu; Chih-Hao Huang; Ya-Jen Chang; Wei-Chien Huang

doi:10.1016/j.omtn.2021.07.022

ERα determines the chemo-resistant function of mutant p53 involving the switch between lincRNA-p21 and DDB2 expressions

Mol Ther Nucleic Acids. 2021 Aug 8:25:536-553. doi: 10.1016/j.omtn.2021.07.022. eCollection 2021 Sep 3.

Authors

Yu-Hao He^{1

2}, Ming-Hsin Yeh^{3

4}, Hsiao-Fan Chen^{2

5}, Tsu-Shing Wang⁶, Ruey-Hong Wong^{7

8}, Ya-Ling Wei², Thanh Kieu Huynh^{2

9}, Dai-Wei Hu^{2

9}, Fang-Ju Cheng^{2

10}, Jhen-Yu Chen², Shu-Wei Hu^{2

9}, Chia-Chen Huang⁷, Yeh Chen^{5

11}, Jiaxin Yu¹², Wei-Chung Cheng^{1

13}, Pei-Chun Shen¹³, Liang-Chih Liu¹⁴, Chih-Hao Huang¹⁴, Ya-Jen Chang^{1

15}, Wei-Chien Huang^{1

2

5

9

13

16}

Affiliations

¹ The PhD Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 40402, Taiwan.
² Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
³ Department of Surgery, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
⁴ Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
⁵ Drug Development Center, China Medical University, Taichung 40402, Taiwan.
⁶ Department of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan.
⁷ Department of Public Health, Chung Shan Medical University, Taichung 40201, Taiwan.
⁸ Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
⁹ Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.
¹⁰ Graduate Institute of Basic Medical Sciences, China Medical University, Taichung 40402, Taiwan.
¹¹ Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan.
¹² AI Innovation Center, China Medical University Hospital, Taiwan 40402, Taiwan.
¹³ Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan.
¹⁴ Division of Breast Surgery, China Medical University Hospital, Taichung 40402, Taiwan.
¹⁵ Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
¹⁶ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan.

Abstract

Mutant p53 (mutp53) commonly loses its DNA binding affinity to p53 response elements (p53REs) and fails to induce apoptosis fully. However, the p53 mutation does not predict chemoresistance in all subtypes of breast cancers, and the critical determinants remain to be identified. In this study, mutp53 was found to mediate chemotherapy-induced long intergenic noncoding RNA-p21 (lincRNA-p21) expression by targeting the G-quadruplex structure rather than the p53RE on its promoter to promote chemosensitivity. However, estrogen receptor alpha (ERα) suppressed mutp53-mediated lincRNA-p21 expression by hijacking mutp53 to upregulate damaged DNA binding protein 2 (DDB2) transcription for subsequent DNA repair and chemoresistance. Levels of lincRNA-p21 positively correlated with the clinical responses of breast cancer patients to neoadjuvant chemotherapy and had an inverse correlation with the ER status and DDB2 level. In contrast, the carboplatin-induced DDB2 expression was higher in ER-positive breast tumor tissues. These results demonstrated that ER status determines the oncogenic function of mutp53 in chemoresistance by switching its target gene preference from lincRNA-p21 to DDB2 and suggest that induction of lincRNA-p21 and targeting DDB2 would be effective strategies to increase the chemosensitivity of mutp53 breast cancer patients.

Keywords: DDB2; G-quadruplex; chemotherapy; estrogen receptor; lincRNA-p21; mutant p53.