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

被引：16

作者：

He, Yu-Hao ^{[1
,2
]}

Yeh, Ming-Hsin ^{[3
,4
]}

Chen, Hsiao-Fan ^{[2
,5
]}

Wang, Tsu-Shing ^{[6
]}

Wong, Ruey-Hong ^{[7
,8
]}

Wei, Ya-Ling ^{[2
]}

Huynh, Thanh Kieu ^{[2
,9
]}

Hu, Dai-Wei ^{[2
,9
]}

Cheng, Fang-Ju ^{[2
,10
]}

Chen, Jhen-Yu ^{[2
]}

Hu, Shu-Wei ^{[2
,9
]}

Huang, Chia-Chen ^{[7
]}

Chen, Yeh ^{[5
,11
]}

Yu, Jiaxin ^{[12
]}

Cheng, Wei-Chung ^{[1
,13
]}

Shen, Pei-Chun ^{[13
]}

Liu, Liang-Chih ^{[14
]}

Huang, Chih-Hao ^{[14
]}

Chang, Ya-Jen ^{[1
,15
]}

Huang, Wei-Chien ^{[1
,2
,5
,9
,13
,16
]}

机构：

[1] China Med Univ & Acad Sinica, PHD Program Canc Biol & Drug Discovery, Taichung 40402, Taiwan

[2] China Med Univ Hosp, Ctr Mol Med, Taichung 40402, Taiwan

[3] Chung Shan Med Univ Hosp, Dept Surg, Taichung 40201, Taiwan

[4] Chung Shan Med Univ, Inst Med, Sch Med, Taichung 40201, Taiwan

[5] China Med Univ, Drug Dev Ctr, Taichung 40402, Taiwan

[6] Chung Shan Med Univ, Dept Biomed Sci, Taichung 40201, Taiwan

[7] Chung Shan Med Univ, Dept Publ Hlth, Taichung 40201, Taiwan

[8] Chung Shan Med Univ Hosp, Dept Occupat Med, Taichung 40201, Taiwan

[9] China Med Univ, Grad Inst Biomed Sci, Taichung 40402, Taiwan

[10] China Med Univ, Inst Basic Med Sci, Taichung 40402, Taiwan

[11] China Med Univ, Inst New Drug Dev, Taichung 40402, Taiwan

[12] China Med Univ Hosp, AI Innovat Ctr, Taichung 40402, Taiwan

[13] China Med Univ, Res Ctr Canc Biol, Taichung 40402, Taiwan

[14] China Med Univ Hosp, Div Breast Surg, Taichung 40402, Taiwan

[15] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan

[16] Asia Univ, Dept Med Lab Sci & Biotechnol, Taichung 41354, Taiwan

来源：

MOLECULAR THERAPY-NUCLEIC ACIDS | 2021年 / 25卷

关键词：

MULTICENTER PHASE-II; LONG NONCODING RNA; ESTROGEN-RECEPTOR; BREAST-CANCER; GENE-EXPRESSION; NEOADJUVANT CHEMOTHERAPY; TP53; GENE; DNA; REPRESSION; PACLITAXEL;

D O I：

10.1016/j.omtn.2021.07.022

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 (ER alpha) 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.

引用

页码：536 / 553

页数：18

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