ACK1 promotes gastric cancer epithelial–mesenchymal transition and metastasis through AKT–POU2F1–ECD signalling

Abstract

Amplification of the activated Cdc42-associated kinase 1 (ACK1) gene is frequent in gastric cancer (GC). However, little is known about the clinical roles and molecular mechanisms of ACK1 abnormalities in GC. Here, we found that the ACK1 protein level and ACK1 phosphorylation at Tyr 284 were frequently elevated in GC and associated with poor patient survival. Ectopic ACK1 expression in GC cells induced epithelial-mesenchymal transition (EMT) and promoted migration and invasion in vitro, and metastasis in vivo; the depletion of ACK1 induced the opposite effects. We utilized SILAC quantitative proteomics to discover that the level of the cell cycle-related protein ecdysoneless homologue (ECD) was markedly altered by ACK1. Overexpression of ECD promoted EMT, migration, and invasion in GC, similar to the effects of ACK1 overexpression. Silencing of ECD completely blocked the augmentation of ACK1 overexpression-induced EMT, migration, and invasion. Mechanistically, ACK1 phosphorylated AKT at Thr 308 and Ser 473 and activated the AKT pathway to up-regulate the transcription factor POU2F1, which directly bound to the promoter region of its novel target gene ECD and thus regulated ECD expression in GC cells. Furthermore, the phosphorylation levels of AKT at Thr 308 and Ser 473 and POU2F1 and ECD levels were positively associated with ACK1 levels in clinical GC specimens. Collectively, we have demonstrated that ACK1 promotes EMT, migration, and invasion by activating AKT-POU2F1-ECD signalling in GC cells. ACK1 may be employed as a new prognostic factor and therapeutic target for GC.

Amplification of ACK1 promotes gastric tumorigenesis via ECD-dependent p53 ubiquitination degradation

“…Our previous study showed that ACK1 protein levels and ACK1 phosphorylation at Tyr 284 were frequently elevated in GC and associated with poor survival in GC patients [16]. Amplification of the ACK1 gene is frequent in breast, lung and ovarian cancers [6, 8].…”

“…To elucidate the molecular mechanism of ACK1 on the regulation of tumor growth and colony formation, 147 differential proteins regulated by ACK1 were previously identified using SILAC quantitative proteomics by our group [16]. Herein, a gene ontology annotation analysis further revealed that 147 differential proteins regulated by ACK1 could be categorized into two main groups (regulation of cell death (survival) and cell migration) according to their associated biological processes (Figure 4).…”

“…Over-expression of ACK1 is associated with cancer progression and metastasis in breast cancer, prostate cancer, non-small-cell lung cancer and hepatocellular carcinoma [5, 10–15]. Our previous study showed that ACK1 is significantly up-regulated in GC compared to adjacent gastric tissues and is associated with a poor prognosis in GC patients [16]. To date, however, the impact of ACK1 on GC tumorigenesis and its molecular mechanisms in GC have not been elucidated.…”

The Oct1 transcription factor and epithelial malignancies: Old protein learns new tricks

“…For instance a recent study by Xu et al . finds that Oct1 is elevated in gastric cancer tissue and is also regulated by the AKT pathway, leading to the induction of epithelial-to-mesenchymal transition (EMT) [92]. EMT is a cellular process observed in cancer progression and metastasis in which biochemical changes in epithelial cells allow them to become more migratory as they acquire mesenchymal cell characteristics [93].…”

Expression of APPL1 Is Correlated with Clinicopathologic Characteristics and Poor prognosis in Patients with Gastric Cancer

“…Concurrently, appl1 actives the Akt pathway by acting as a scaffold protein that interacts with GIPC1, one of GIPC family members 24 . After phosphorylation, Akt phosphorylates the activated Cdc42-associated kinase 1, induces reactions in cells, and promotes tumour growth 25 . The activation of glycogen synthase kinase 3β, which depends on the Akt pathway, impedes cell apoptosis in gc 26 .…”