ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Abstract

Activation of phosphatidylinositol 3 kinase (PI3K), Ras, and Her2 signaling plays a critical role in cancer development. Hotspot constitutive activating mutations in oncogenes, such as PIK3CA encoding the p110α catalytic subunit or RAS, as well as overexpression of Her2, are frequently found in human tumors and cancers. It has been well established that activation of these oncogenes profoundly promotes tumor metastasis, whereas decreased expression of ΔNp63α, the major protein isoform of the p53-related p63 expressed in epithelial cells, has been associated with cancer metastasis. In this study, we demonstrate that hotspot oncogenic mutations on PIK3CA and RAS, including p110α H1047R , K-Ras G12V , and H-Ras G12V , as well as activation of Her2, all led to suppression of ΔNp63α expression via Akt-fork-head transcription factor 3a (Akt-FOXO3a) signaling, resulting in increased cell motility and tumor metastasis. Expression of ΔNp63α effectively reversed p110α H1047R -, K-Ras G12V -, H-Ras G12V -, or Her2-induced cell motility in vitro and tumor metastasis in mouse models. We show that ΔNp63α was a direct FOXO3a transcriptional target and that expression of FOXO3a and ΔNp63α was correlated in human cancer biopsy samples. Together, these results demonstrate that ΔNp63α is a common inhibitory target of oncogenic PI3K, Ras, and Her2, and that ΔNp63α may function as a critical integrator of oncogenic signaling in cancer metastasis.PIK3CA | Ras | Her2 | ΔNp63α | cancer metastasis

Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation

“…Therefore, we hypothesized that AMPKα1 expression is likely inhibited at the transcriptional level. Notably, hotspot constitutive active mutations of PIK3CA, exemplified as p110α H1047R , or overexpression of HER2 are frequently found in human breast cancers, which have been documented to drive breast cancer metastasis (19,21,22). To investigate a possible connection between oncogenic PI3K/HER2 and AMPKα1 expression, we expressed p110α H1047R or constitutive active HER2 V659E in MCF10A or HCC1806 cells.…”

“…ΔNp63α, the predominant p63 isoform expressed in epithelia, is a critical transcription factor regulating expression of genes involved in cell adhesion, including E-cadherin, integrin α6, integrin β4, integrin α5, desmoplakin, and fibronectin (17)(18)(19). Clinical evidence indicates that expression of ΔNp63α is reduced in advanced cancers (19). Our previous study has demonstrated that ΔNp63α is a common inhibitory target of PI3K/Ras/HER2 and functions as a critical metastasis inhibitor (19).…”

“…Clinical evidence indicates that expression of ΔNp63α is reduced in advanced cancers (19). Our previous study has demonstrated that ΔNp63α is a common inhibitory target of PI3K/Ras/HER2 and functions as a critical metastasis inhibitor (19).…”

“…There are multiple p63 protein isoforms, derived from alternative transcription start sites at the N termini and alternative splicing at C termini (16). ΔNp63α, the predominant p63 isoform expressed in epithelia, is a critical transcription factor regulating expression of genes involved in cell adhesion, including E-cadherin, integrin α6, integrin β4, integrin α5, desmoplakin, and fibronectin (17)(18)(19). Clinical evidence indicates that expression of ΔNp63α is reduced in advanced cancers (19).…”

RETRACTED ARTICLE: Ras-ERK1/2 signalling promotes the development of osteosarcoma through regulation of H4K12ac through HAT1

“…Ras (rat sarcoma viral oncogene homolog) is known to be a kind of conserved oncogene, which can activate the downstream signalling pathway by increasing expression, gene point mutation, gene insertion and translocation [5,6]. Activation of Ras has been found in various cancers, which is implicated in mediating different biological processes, including cell proliferation, apoptosis and metastasis [7,8]. With regard to OS, Ras activation has been reported to regulate WISP-1-enhanced cell migration and matrix metalloproteinases (MMPs) expression in OS [9].…”