The Role of PHLDA3 in Cancer Progression and Its Potential as a Therapeutic Target

Abstract

Pleckstrin homology-like domain family A, member 3 (PHLDA3) is a p53-regulated tumor suppressor protein that suppresses AKT-mediated survival and oncogenic signaling. The PHLDA3 gene has garnered significant attention due to its multifaceted roles in tumorigenesis, metastasis, and invasion. This review explores the complex interactions between PHLDA3 and key cellular processes involved in cancer, emphasizing its regulatory mechanisms and clinical relevance. PHLDA3 has been found to be a critical regulator of metastatic pathways, particularly through its influence on the epithelial-mesenchymal transition (EMT) and in cellular invasion. Its interactions with pivotal signaling pathways, such as the Phosphoinositide 3-kinases/Protein kinase B (PI3K/AKT), p53, and Wnt/β-catenin pathways, highlight its multifunctional roles in various cancer types. Additionally, we discuss the potential of PHLDA3 as both a prognostic biomarker and a therapeutic target, offering new insights into its potential in treating advanced-stage malignancies. This review provides a detailed analysis of the role of PHLDA3 in cancer progression, including metastasis and invasion, underscoring its therapeutic potential.

Keywords: AKT pathway; PHLDA3; invasion; metastasis; p53; tumor progression.

Figure 1

Role of PHLDA3 in the PI3K/AKT signaling pathway. (A) A schematic diagram of PHLDA3. PH–Pleckstrin Homology. (B) Growth factor stimulation activates PI3K, which converts PIP2 into PIP3, facilitating AKT recruitment to the cell membrane via its PH domain. PHLDA3 competitively binds to PIP3, thereby inhibiting AKT activation and downstream signaling. p53 binds to PHLDA3 and regulates its expression at the transcriptional level.

Figure 2

PHLDA3 and Wnt signaling pathway. PHLDA3 is shown to influence this pathway by regulating β-catenin stability and activity. In the absence of AKT activation, GSK3β remains active, facilitating the proteasomal degradation of β-catenin. When AKT becomes phosphorylated and activated, it inhibits GSK3β through phosphorylation at Ser9, preventing β-catenin degradation. Stabilized β-catenin translocates to the nucleus, where it interacts with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to drive the expression of its target genes. PHLDA3 is depicted as a key regulator in this cascade, fine-tuning the balance between β-catenin degradation and activation.

Figure 3

Dual function of PHLDA3 as both an apoptosis inducer and inhibitor. (A) Under hypoxic conditions, p53 is activated through phosphorylation. This activation of p53 subsequently induces the expression of PHLDA3. Once expressed, PHLDA3 inactivates AKT, leading to the induction of apoptosis. (B) Upon ER stress, XBP1 upregulates PHLDA3, which suppresses pro-inflammatory pathways by inhibiting the expression of NFκB and iNOS, reducing the production of inflammatory mediators like nitric oxide (NO). Additionally, PHLDA3 helps alleviate oxidative stress by promoting the mRNA expression of key antioxidant genes, such as Gpx1 and Srxn1, which regulate ROS levels. Through these mechanisms, PHLDA3 supports β cell survival by preventing apoptosis induced by inflammation and oxidative damage.

Figure 4

Role of PHLDA3 in SCC progression. PHLDA3 expression suppresses the development of papilloma and metastasis of SCC.

Figure 5

Defects in the PHLDA3 gene are observed in PanNETs. (A) PanNETs may experience two-hit inactivation of PHLDA3 through LOH and methylation at its loci. (B) Tumorigenesis in PanNETs requires the loss of both PHLDA3 and MEN1 function, as these genes normally restrain cell proliferation in islet cells. (C) The progressive development of PanNETs involves the functional loss of PHLDA3 alongside MEN1, leading to islet abnormalities and eventual tumorigenesis.