Low PIP4K2B Expression in Human Breast Tumors Correlates with Reduced Patient Survival: A Role for PIP4K2B in the Regulation of E-Cadherin Expression

Abstract

Phosphatidylinositol-5-phosphate (PtdIns5P) 4-kinase b (PIP4K2B) directly regulates the levels of two important phosphoinositide second messengers, PtdIns5P and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P 2 ]. PIP4K2B has been linked to the regulation of gene transcription, to TP53 and AKT activation, and to the regulation of cellular reactive oxygen accumulation. However, its role in human tumor development and on patient survival is not known. Here, we have interrogated the expression of PIP4K2B in a cohort (489) of patients with breast tumor using immunohistochemical staining and by a meta-analysis of gene expression profiles from 2,999 breast tumors, both with associated clinical outcome data. Low PIP4K2B expression was associated with increased tumor size, high Nottingham histological grade, Ki67 expression, and distant metastasis, whereas high PIP4K2B expression strongly associated with ERBB2 expression. Kaplan-Meier curves showed that both high and low PIP4K2B expression correlated with poorer patient survival compared with intermediate expression. In normal (MCF10A) and tumor (MCF7) breast epithelial cell lines, mimicking low PIP4K2B expression, using short hairpin RNA interference-mediated knockdown, led to a decrease in the transcription and expression of the tumor suppressor protein E-cadherin (CDH1). In MCF10A cells, knockdown of PIP4K2B enhanced TGF-b-induced epithelial to mesenchymal transition (EMT), a process required during the development of metastasis. Analysis of gene expression datasets confirmed the association between low PIP4K2B and low CDH1expression. Decreased CDH1 expression and enhancement of TGF-b-induced EMT by reduced PIP4K2B expression might, in part, explain the association between low PIP4K2B expression and poor patient survival. Cancer Res; 73(23); 6913-25. Ó2013 AACR.

Differential profile of PIP4K2A expression in hematological malignancies

“…Similar association was observed for PIP4K2B in breast cancer: PIP4K2A/B inhibition reduces cell viability in p53-null breast cancer cells [11], but low expression of PIP4K2B expression was associated with increased tumor size, proliferation markers, distant metastasis and reduced survival in breast cancer patients [23].…”

“…Furthermore, our results in Namalwa cells highlighted the importance of the study of PIP4K2A inhibition in different cell models and cell signaling background, including the constitutive PI3K/AKT activation, to attempt to better define the potential cell types responsive to inhibition PIP4K2A. It is important to point out that HEL [21] and Namalwa [22,23] cells have mutated p53, which has been reported to modulate the response to PIPK inhibition [11].…”

The Hidden Conundrum of Phosphoinositide Signaling in Cancer

“…Like PIPKIs, deep transcriptome sequencing shows increased expression of PIPKII in cancer cells and cancer tissues [54]. PIP4KIIα and PIP4KIIβ are over-expressed in HER2-positive breast cancer tissues [55], and ACGH array shows the amplification of PIP4KIIβ gene as part of HER2 amplicon in cancer [56]. These lipid kinases appear essential for tumor growth in the background of p53 loss or mutations.…”

The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis

“…1 A and B), while other families of phosphoinositide kinases (PI4P5K/Type I PIPK and PI3P5K/Type III PIPK/PIKfyve) were not detected. PI5P4Ks, an emerging target for cancer therapy, control the levels of lipid second messenger, PI(5)P (Clarke and Irvine, 2013; Emerling et al, 2013; Jude et al, 2015; Keune et al, 2013). These results raised the possibility that PI5P4Ks have an intrinsic ability to bind to GTP.…”

“…It has been shown that solid tumor cells need to adapt their metabolism in order to cope with nutrient and energy stresses during tumorigenesis (Cantor and Sabatini, 2012; Jones and Thompson, 2009; Laderoute et al, 2006; Schafer et al, 2009). PI5P4Ks have been shown to promote tumorigenesis in several types of cancers (Emerling et al, 2013; Jude et al, 2015; Keune et al, 2013; Luoh et al, 2003), raising the possibility that the GTP-sensing activity of PI5P4Kβ is involved in its tumorigenic activity. Thus, we compared anchorage-independent soft-agar colony formation of WT-PI5P4Kβ cells to that of PI5P4Kβ F205L cells, where cells are exposed to similar nutrient depleted conditions as cancer cells in tissues (Paoli et al, 2013; Schafer et al, 2009).…”