ERα determines the chemo-resistant function of mutant p53 involving the switch between lincRNA-p21 and DDB2 expressions
| Autor: | Liang Chih Liu, Thanh Kieu Huynh, Pei-Chun Shen, Fang-Ju Cheng, Dai-Wei Hu, Ruey-Hong Wong, Wei Chien Huang, Jiaxin Yu, Ya-Ling Wei, Ya-Jen Chang, Wei-Chung Cheng, Yeh Chen, Chih-Hao Huang, Chia-Chen Huang, Jhen-Yu Chen, Shu-Wei Hu, Hsiao-Fan Chen, Yu-Hao He, Ming-Hsin Yeh, Tsu-Shing Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
G-quadruplex
DNA repair Mutant mutant p53 Estrogen receptor DDB2 RM1-950 Biology medicine.disease chemotherapy Damaged DNA binding Breast cancer Downregulation and upregulation Transcription (biology) Drug Discovery Cancer research medicine Molecular Medicine Original Article Therapeutics. Pharmacology lincRNA-p21 Estrogen receptor alpha estrogen receptor |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 25, Iss, Pp 536-553 (2021) Molecular Therapy. Nucleic Acids |
| ISSN: | 2162-2531 |
| Popis: | 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. Graphical abstract ER status determines the oncogenic function of mutp53 in chemoresistance by switching its target gene preference from lincRNA-p21 to DDB2. The co-treatment of chemotherapy with ER antagonists in a neoadjuvant setting may benefit luminal A/B patients through upregulation of lincRNA-p21 to enhance chemotherapy efficacy in mutp53-expressing breast cancers. |
| Databáze: | OpenAIRE |
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