GABAB receptor inhibits tumor progression and epithelial-mesenchymal transition via the regulation of Hippo/YAP1 pathway in colorectal cancer

Abstract

Gamma-Aminobutyric Acid Type B Receptor (GABABR) plays essential roles in tumor progression. However, the function of GABABR in colorectal cancer (CRC) needs further clarification. As the main part of GABABR, GABABR1 expression was identified significantly lower in tumor tissues than those in non-tumor normal tissues and that CRC patients with high GABABR1 expression lived longer. Further studies indicated that knockdown of GABABR1 elevated CRC cell proliferation, migration, and invasion. Furthermore, knockdown of GABABR1 activated the expression of the epithelial-mesenchymal transition (EMT)-related proteins N-cadherin and Vimentin, whereas decrease the protein level of E-cadherin. In addition, activation of Hippo/YAP1 signaling contributes to the GABABR1 down-regulation promoted proliferation, migration, invasion and EMT in CRC cells. At last, we verified the contribution of Hippo/YAP1 signaling in the GABABR1 down-regulation impaired biological phenotype of colon cancer cells in vivo . In summary, these data indicate that GABABR1 impairs the migration and invasion of CRC cells by inhibiting EMT and the Hippo/YAP1 pathway, suggesting that GABABR1 could be a potential therapeutic target for CRC.

Insertion of the CXXC domain of KMT2A into YAP1: An unusual mechanism behind the formation of a chimeric oncogenic protein

“…31,32 Cadherin signaling functions as a stimulator of the Hippo pathway and regulates YAP1. 33 GABA-B I receptors are known to be transcriptional regulators of YAP1 in colorectal cancer 34 ; however, the role of GABA-B II receptors is yet unclear. Overall, our findings suggest activation of multiple oncogenic pathways in YKY tumors, likely due to their association with YAP1.…”

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

“…In fact, the transcriptional activity of YAP appears to be controlled by a growing number of upstream regulators including several members of the WWC-and-C2 domain-containing protein family (Höffken et al, 2021). Recent findings have highlighted the role of several modulators of the Hippo signaling pathway, including the high mobility group AT-hook 2 (HMGA2), a DNA binding protein , the scribble planar cell polarity protein (SCRIB) , and GABABR1, one of the two subunits making up the GABA B receptor (Wang H. et al, 2021b). The upregulation of receptor of collagen I, Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), also confers a susceptibility to ferroptosis via the Hippo pathway (Lin C. C. et al, 2021).…”

The Nervous System Contributes to the Tumorigenesis and Progression of Human Digestive Tract Cancer

“…Additionally, the inhibition of the receptor, an opposite measure, is used in prostate cancer aimed at EGFR lines [71]. In CRC, GABBR1-related research unveils a Hippo/YAP1 signaling pathway to demonstrate that GABBR1 inhibits the development of CRC and indirectly shows the feasibility of treatment targeting GABBR1 [72] (Figure 2). A study pointed out the prospects of GABAA receptors [73], and this article listed the complex internal connection of GABAA receptors and different organs.…”