Krüppel-like Factor 4 (KLF4) Activates the Transcription of the Gene for the Platelet Isoform of Phosphofructokinase (PFKP) in Breast Cancer

Abstract

Krü ppel-like factor 4 (KLF4) is a transcription factor that plays an important role in cell differentiation, proliferation, and survival, especially in the context of cancers. This study revealed that KLF4 activates glycolytic metabolism in breast cancer cells by up-regulating the platelet isoform of phosphofructokinase (PFKP). KLF4 activated the transcription of the PFKP gene by directly binding to the PFKP promoter. Whereas glucose uptake and lactate production were inhibited by the knockdown of KLF4, they were activated by the overexpression of KLF4. Unlike PFKP, the expressions of the other isoforms of phosphofructokinase and glycolytic genes were unaffected by KLF4. The human breast cancer tissues showed a close correlation between KLF4 and PFKP expression. This study also showed that PFKP plays a critical role in cell proliferation in breast cancer cells. In conclusion, it is suggested that KLF4 plays a role in maintenance of high glycolytic metabolism by transcriptional activation of the PFKP gene in breast cancer cells.Breast cancer is the most common type of cancer in women in Western countries (1). Breast cancer shows elevated glycolytic metabolism, which is one of the common characteristics of the malignant cancers (2). The increase in glycolytic rate is a result of the up-regulation of the metabolic transporters and glycolytic enzymes whose expressions are controlled by the transcriptional regulation of genes as well as post-translational modifications of the enzymes (2, 3).The conversion of fructose 6-phosphate to fructose 1,6-bisphosphate is the first committed step in the glycolytic pathway catalyzed by phosphofructokinase (PFK-1) (4, 5). PFK-1 is a complex tetrameric enzyme and exists in three isoforms: liver (PFKL), muscle (PFKM), and platelet (PFKP). The activity of PFK-1 is regulated by both quantitative changes and isozymic alterations secondary to altered gene expression during neoplastic transformation in vivo and in vitro (6, 7). The expression of PFK-1 is up-regulated in cancer cells, where glycolysis is enhanced (7,8). Although an increase in PFKP expression is a characteristic feature of malignant tissues (8), little is known about how PFKP expression is regulated during the development and progression of cancers or the change of cancer phenotypes.Krüppel-like factor 4 (KLF4) is a transcriptional factor that modulates the expression of several genes that are involved in cell cycle regulation and differentiation (9, 10). The KLF4 levels rise following DNA damage, cell cycle arrest in response to serum withdrawal, and contact inhibition (10). Elevated KLF4 level has also attributed to certain types of cancers. KLF4 mRNA and protein are overexpressed in up to 70% of breast cancers (11,12). The increased nuclear expression of KLF4 is considered to be associated with the aggressiveness of breast cancer phenotypes (12). KLF4 has been found to be overexpressed in oral and skin squamous carcinoma cells as well (13). In addition, KLF4 exhibits potent transforming activity when expressed in cult...

The transcription factor KLF4 as an independent predictive marker for pathologic complete remission in breast cancer neoadjuvant chemotherapy: a case–control study

“…The fact that KLF4 overexpression resulted in worse survival has been demonstrated by many clinical data, and the reason has been widely discussed. Some recent studies suggested that KLF4 participates in many signaling pathways that support multiple aggressive traits in breast cancer, such as maintenance of high glycolytic metabolism27 and upregulation of Notch signaling 11,28. The present study indicates that high KLF4 expression leads to a worse outcome possibly due to resistance of chemotherapy.…”

Metabolic differences in breast cancer stem cells and differentiated progeny

“…In these studies it was demonstrated that in breast cancer cells, KLF4 activates the transcription of the PFK-P gene directly by binding to its promoter [19]. To investigate the expression of the PFK gene in our system we performed qRT-PCR analysis in two different breast cancer lines in sorted differentiated cells (ZsGreen-cODC-neg) and sorted BCSCs (ZsGreen-cODC-pos).…”

Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists

“…Glyceraldehyde-3-phosphate dehydrogenase, decreased in ADP induced activation, was shown to be required for the transport of nitric oxide in platelets [49]. ATP-dependent 6-phosphofructokinase platelet type, also found to be less abundant in ADP induced PMPs, was shown to play a critical role in cell proliferation in breast cancer cells [50]. A small group Fig.…”