WBP2 promotes gastric cancer cell migration via novel targeting of LATS2 kinase in the Hippo tumor suppressor pathway

Abstract

Dysregulation of signaling pathways is responsible for many human diseases. The lack of understanding of the molecular etiology of gastric cancer (GC) poses a substantial challenge to the development of effective cancer therapy. To better understand the molecular mechanisms underlying the pathogenesis of GC, which will facilitate the identification and development of effective therapeutic approaches to improve patient outcomes, mass spectrometry-based phosphoproteomics analysis was performed to map the global molecular changes in GC. A total of 530 proteins with altered phosphorylation levels were detected across a panel of 15 normal and GC cell lines. WW domain-binding protein 2 (WBP2) was validated to be upregulated in a subset of GC cell lines. WBP2 is overexpressed in 61% cases of GC compared to non-cancer tissues and high WBP2 expression correlates with poor clinical outcomes. WBP2 was found to be required for GC cell migration but is dispensable for cell growth and proliferation. WBP2 knockdown increased p-LATS2 with a concomitant increase in p-YAP, resulting in the cytoplasmic retention of YAP and ultimately the inhibition of YAP/TEAD activity and downregulation of TEAD target genes--CTGF and CYR61. Importantly, the loss of LATS2 reversed the activation of Hippo pathway caused by WBP2 knockdown, indicating that WBP2 acts through LATS2 to exert its function on the Hippo pathway. Moreover, WBP2 interacted with LATS2 to inhibit its phosphorylation and activity. In conclusion, our study established a pivotal role for WBP2 in the promotion of GC cell migration via a novel mechanism that inactivates the Hippo pathway transducer LATS2.

Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy

“…In a similar fashion, elevated WBP2 protein expression was also observed in the more aggressive gastric cancer cell lines as compared to the less aggressive ones [71]. Concurrently, in vitro and in vivo studies demonstrated that WBP2 was a promoter of cancer proliferation, migration and invasion [70][71][72][73][74]. In glioma cells, WBP2 regulates α enolase-mediated glycolysis to aggravate cell proliferation and migration [74].…”

“…The oncogenic roles of WBP2 were initially studied in breast cancer and subsequently explored in other cancers such as squamous cell carcinoma, brain, liver, gastric and lung cancers. Figure 3B summarises some of the key evidence that positions WBP2 as a driver Besides breast cancer, WBP2 overexpression has also been observed in tumours of the liver, stomach, lung and skin, compared to adjacent normal tissues, through IHC experiments [70][71][72][73]. Furthermore, WBP2 status was positively associated with higher pathological stages and poorer survival in human glioma, gastric and non-small cell lung carcinoma (NSCLC) patients [25,71,72] (Figure 3B).…”

“…Figure 3B summarises some of the key evidence that positions WBP2 as a driver Besides breast cancer, WBP2 overexpression has also been observed in tumours of the liver, stomach, lung and skin, compared to adjacent normal tissues, through IHC experiments [70][71][72][73]. Furthermore, WBP2 status was positively associated with higher pathological stages and poorer survival in human glioma, gastric and non-small cell lung carcinoma (NSCLC) patients [25,71,72] (Figure 3B). In a similar fashion, elevated WBP2 protein expression was also observed in the more aggressive gastric cancer cell lines as compared to the less aggressive ones [71].…”

“…Furthermore, WBP2 status was positively associated with higher pathological stages and poorer survival in human glioma, gastric and non-small cell lung carcinoma (NSCLC) patients [25,71,72] (Figure 3B). In a similar fashion, elevated WBP2 protein expression was also observed in the more aggressive gastric cancer cell lines as compared to the less aggressive ones [71]. Concurrently, in vitro and in vivo studies demonstrated that WBP2 was a promoter of cancer proliferation, migration and invasion [70][71][72][73][74].…”

“…To obtain a more comprehensive view of WBP2 in cancer, our meta-analysis based on the TCGA Pan-Cancer Atlas revealed that WBP2 amplification was observed at high frequencies in approximately 78% of 32 cancer types (Figure 4) [68]. These include hepatocellular carcinoma, non-small cell lung cancer, glioma and gastric cancer [70][71][72], where WBP2 has already been reported to be functionally implicated. Moreover, WBP2 amplification was found in several other cancers, such as ovarian, cervical and pancreatic cancers.…”