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

Abstract

ObjectivesThe present study aims to elucidate the underlying mechanism how PFKP is regulated by BRCA1 and the clinical significance of PFKP in breast cancer. MethodsMEF-BRCA1 4/4 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. ResultsWe found that MEF-BRCA1 4/4 cells consumed more glucose and were more vulnerable to glucose-deprived culture medium. The mRNA profiles and qPCR assay of MEF-BRCA1 4/4 and MEF-BRCA1 +/+ cells revealed that PFKP, the rate-limiting enzyme of glycolysis, was significantly upregulated in MEF-BRCA1 4/4 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 corepression 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.

Prognostic Roles of Phosphofructokinase Platelet in Clear Cell Renal Cell Carcinoma and Correlation with Immune Infiltration

“…However, further experiments were needed to explore how high PFKP expression improves outcomes in ccRCC patients, which was not consistent with other studies in other types of cancer. 10,12,36 In any case, we provided a newly exciting insight into understanding the role of PFKP in ccRCC.…”

“…34,35 Shen et al 10 found that PFKP regulated the level of glycolysis in lung cancer and was associated with tumor size, proliferation, and patient prognosis. PFKP also has been demonstrated to increase the risk of poor prognosis in breast cancer patients 36 and promote the malignant proliferation of OSCC. 9 Meanwhile, it was noteworthy that the high expression of PFKP was considerably associated with a good prognosis in ccRCC patients.…”

Seven interferon gamma response genes serve as a prognostic risk signature that correlates with immune infiltration in lung adenocarcinoma

“…PFKP is up-regulated in lung cancer and regulates glucose metabolism [ 31 ]. It is a prognostic marker in breast cancer [ 32 ]. LATS2 encodes a serine/threonine protein kinase.…”

KRAB-ZFP Transcriptional Regulators Acting as Oncogenes and Tumor Suppressors: An Overview

“…Recently, two additional ZBRK1 target genes, which are implicated in cellular metabolism, were found to be directly bound and repressed by ZBRK1/BRCA1 transcriptional repressor complex: Phosphofructokinase P ( PFKP ) [ 93 ] and Glutamate-oxaloacetate Transaminase 2 ( GOT2 ) [ 94 ]. Both genes were shown overexpressed in BRCA, causing glycolysis dysregulation and increased aspartate metabolism, respectively.…”

“…Both genes were shown overexpressed in BRCA, causing glycolysis dysregulation and increased aspartate metabolism, respectively. Reduced ZBRK1/BRCA1 activity on their promoters resulted in PFKP and GOT2 upregulation, which was associated with adverse outcomes in BRCA patients [ 93 , 94 ]. BRCA1/ZBRK1 duet was shown as well to interact with another transcriptional co-repressor, namely CtBP-interacting protein (CtIP).…”