Abstract
BackgroundThe human positive cofactor 4 (PC4) is initially identified as a transcriptional cofactor and has an important role in embryonic development and malignant transformation. However, the clinical significance and the molecular mechanisms of PC4 in breast cancer development and progression are still unknown.MethodsWe investigated PC4 expression in 114 cases of primary breast cancer and matched normal breast tissue specimens, and studied the impact of PC4 expression as well as the molecular mechanisms of this altered expression on breast cancer growth and metastasis both in vitro and in vivo.ResultsPC4 was significantly upregulated in breast cancer and high PC4 expression was positively correlated with metastasis and poor prognosis of patients. Gene set enrichment analysis (GSEA) demonstrated that the gene sets of cell proliferation and Epithelial-Mesenchymal Transition (EMT) were positively correlated with elevated PC4 expression. Consistently, loss of PC4 markedly inhibited the growth and metastasis of breast cancer both in vitro and in vivo. Mechanistically, PC4 exerted its oncogenic functions by directly binding to c-Myc promoters and inducing Warburg effect.ConclusionsOur study reveals for the first time that PC4 promotes breast cancer progression by directly regulating c-Myc transcription to promote Warburg effect, implying a novel therapeutic target for breast cancer.
Highlights
The human positive cofactor 4 (PC4) is initially identified as a transcriptional cofactor and has an important role in embryonic development and malignant transformation
PC4 is significantly upregulated in breast cancer and is closely correlated with metastasis and poor prognosis of patients To explore the potential clinical significance of PC4, we firstly detected PC4 expression level in 114 cases of breast cancer patients compared with their adjacent counterparts
In both invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), aberrant PC4 overexpression was observed in carcinoma tissues from immunohistochemistry results, while weak positive signal was found in adjacent tissues and almost no positive signal in normal tissues (Fig. 1a)
Summary
The human positive cofactor 4 (PC4) is initially identified as a transcriptional cofactor and has an important role in embryonic development and malignant transformation. The clinical significance and the molecular mechanisms of PC4 in breast cancer development and progression are still unknown. Many patients still develop into metastatic disease, which is the leading cause of breast cancer death [1,2,3]. There is an urgent need to characterize the underlying molecular mechanisms and identify novel therapeutic targets to improve the outcomes for breast cancer [4]. The Warburg effect [6], as known as aerobic glycolysis, is the best-characterized metabolic change in cancer cells, which facilitates cancer growth and progression by increasing glucose uptake, elevating lactate production, and supporting the energy demands [7]. Emerging evidence has indicated the crucial role of the Warburg effect in cancer therapy as a novel target [8]. A few transcription factors have been reported to regulate glycolysis [11], the transcriptional regulation of Warburg effect
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