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PFKP is transcriptionally repressed by BRCA1/ZBRK1 and predicts prognosis in breast cancer.

Authors :
Danna Yeerken
Ruoxi Hong
Yan Wang
Ying Gong
Rui Liu
Di Yang
Jinting Li
Jiawen Fan
Jie Chen
Weimin Zhang
Qimin Zhan
Source :
PLoS ONE, Vol 15, Iss 5, p e0233750 (2020)
Publication Year :
2020
Publisher :
Public Library of Science (PLoS), 2020.

Abstract

OBJECTIVES:The present study aims to elucidate the underlying mechanism how PFKP is regulated by BRCA1 and the clinical significance of PFKP in breast cancer. METHODS:MEF-BRCA1△/△ and the wild type counterpart MEF-BRCA1+/+ cell lines were used to test the sensitivity of glucose depletion in culture medium. Glucose Assay Kit was used to quantify glucose levels in cultural supernatant and cell lysate. Real time PCR was used to measure the mRNA expression levels of genes. Western blot was used to detect protein levels. Chromatin immunoprecipitation was used to verify the bindings between transcription factors and DNA elements. Luciferase reporter assay was performed to determine the transcriptional activity. Histochemistry assay was performed on tissue microarray. RESULTS:We found that MEF-BRCA1△/△ cells consumed more glucose and were more vulnerable to glucose-deprived culture medium. The mRNA profiles and qPCR assay of MEF-BRCA1△/△ and MEF-BRCA1+/+ cells revealed that PFKP, the rate-limiting enzyme of glycolysis, was significantly upregulated in MEF-BRCA1△/△ cells. Consistently, the repressive effects of BRCA1 on PFKP were confirmed by overexpression or knockdown of BRCA1. Moreover, we also demonstrated that PFKP was suppressed by ZBRK1 as well, which was the co-repression partner of BRCA1. Mechanistically, we figured out that BRCA1 formed a transcriptional repression complex with ZBRK1 on the promoter of PFKP and consequently restrained its expression. Importantly, the expression levels of PFKP were demonstrated to associate with poor survival of patients with breast cancer. CONCLUSION:Our study provided a new insight into the dysregulation of glycolysis in breast cancer, which might be partially due to the deficiency of BRCA1/ZBRK1 axis and subsequently reversed the transcriptional repressive effect on PFKP. We also found that PFKP overexpressed in a subset of breast cancer patients and could serve as a prognostic factor, which represented a potential target for BC therapy.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
15
Issue :
5
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.0203b41e04274fddaac5185259f779df
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0233750