PIP4K2A as a negative regulator of PI3K in PTEN-deficient glioblastoma

Abstract

Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.

The prediction of survival in Gastric Cancer based on a Robust 13-Gene Signature

“…CTNNAL1 can contribute to drug-resistance of melanoma through the way of activating NF-κB and AP-1 28 . Shin et al believed that PIP4K2A played a negative regulatory role on PI3K in PTEN-deficient glioblastoma 29 . Emerging evidence has shown that High CST6 expression predicts poor prognosis in Triple-Negative Breast Cancer 30 .…”

New hints towards a precision medicine strategy for IDH wild-type glioblastoma

“…EGFRvIII functions to accelerate tumour growth and proliferation, 52 whereas PTEN-related dysregulation of AKT/protein kinase B signalling cascade results in dysregulated cellular proliferation and aberrant mTOR activation. 53 Early evidence therefore suggested that targeting PTEN, mTOR and EGFR signalling cascades could hold promise; however, this approach has thus far proved underwhelming. 54 These failures are exemplified when one considers the limited clinical effects observed with the tyrosine kinase inhibitors gefitinib, afatinib and lapatinib.…”

Thermal proteome profiling identifies PIP4K2A and ZADH2 as off‐targets of Polo‐like kinase 1 inhibitor volasertib

“…Initial studies of different subtypes of PIP4Ks indicated a potential role of PIP4K2A as an anticancer target in leukemia 41 as it was shown that PIP4K2A knockdown in p53‐mutated tumors reduced the tumor size and increased the tumor‐free survival 42,43 . However, recent studies indicate a potential tumor‐suppressive role of PIP4K2A due to its silencing in leukemia and glioblastoma cells 40,44,45 . Therefore, the question regarding the possibility of using PIP4K2A‐targeted drugs remains open.…”