A novel tumor suppressor ZBTB1 regulates tamoxifen resistance and aerobic glycolysis through suppressing HER2 expression in breast cancer
| Autor: | Kai Qian, Xiaoyi Fu, Yutao Yang, Panhong Zhang, Xiumei Zhang, Qiongqing Liu, Huan Chen, Cuiping Zhang, Shengnan Cao, Lianlian Li, Jiajun Cui |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genome instability 030102 biochemistry & molecular biology Estrogen receptor Cell Biology Biology medicine.disease_cause medicine.disease Biochemistry 03 medical and health sciences 030104 developmental biology Breast cancer Selective estrogen receptor modulator microRNA Cancer cell Cancer research medicine skin and connective tissue diseases Carcinogenesis Molecular Biology Tamoxifen medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 295:14140-14152 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra119.010759 |
| Popis: | Transcriptional repressor zinc finger and BTB domain containing 1 (ZBTB1) is required for DNA repair. Because DNA repair defects often underlie genome instability and tumorigenesis, we determined to study the role of ZBTB1 in cancer. In this study, we found that ZBTB1 is down-regulated in breast cancer and this down-regulation is associated with poor outcome of breast cancer patients. ZBTB1 suppresses breast cancer cell proliferation and tumor growth. The majority of breast cancers are estrogen receptor (ER) positive and selective estrogen receptor modulators such as tamoxifen have been widely used in the treatment of these patients. Unfortunately, many patients develop resistance to endocrine therapy. Tamoxifen-resistant cancer cells often exhibit higher HER2 expression and an increase of glycolysis. Our data revealed that ZBTB1 plays a critical role in tamoxifen resistance in vitro and in vivo. To see if ZBTB1 regulates HER2 expression, we tested the recruitments of ZBTB1 on HER2 regulatory sequences. We observed that over-expressed ZBTB1 occupies the estrogen receptor α (ERα)-binding site of the HER2 intron in tamoxifen-resistant cells, suppressing tamoxifen-induced transcription. In an effort to identify potential microRNAs (miRNAs) regulating ZBTB1, we found that miR-23b-3p directly targets ZBTB1. MiR-23b-3p regulates HER2 expression and tamoxifen resistance via targeting ZBTB1. Finally, we found that miR-23b-3p/ZBTB1 regulates aerobic glycolysis in tamoxifen-resistant cells. Together, our data demonstrate that ZBTB1 is a tumor suppressor in breast cancer cells and that targeting the miR-23b-3p/ZBTB1 may serve as a potential therapeutic approach for the treatment of tamoxifen resistant breast cancer. |
| Databáze: | OpenAIRE |
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