AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis

Abstract

Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1-YAP1-CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograftformation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1-CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.

Identification of YAP1 as a novel downstream effector of the FGF2/STAT3 pathway in the pathogenesis of renal tubulointerstitial fibrosis

“…Reports (Seo et al, 2016) have indicated that YAP1 activation can lead to EMT changes in renal tubular epithelial cells. In this study, we found that consistent with its involvement in the pathogenesis of tumors The expression of FGF2, p-STAT3, STAT3, and YAP1 in the renal tissues of mice in the sham, UUO, N + U, and A + U groups was detected by immunohistochemical staining (×200) (Anna et al 2016;Kang et al, 2018;Zhou et al, 2020), YAP1 promotes the transcription of CTGF, which is a key factor in the pathogenesis of TIF. In this study, we found that the FGF2/STAT3 pathway targeted YAP1 to promote EMT in renal tubular epithelial cells by promoting CTGF expression, which led to the occurrence of renal interstitial fibrosis.…”

“…Yap/Taz activation has been reported to lead to ECM deposition and affect the development and progression of interstitial fibrosis in a mouse model of progressive TIF (Liang et al, 2017). In the pathogenesis of gastric cancer and breast cancer, YAP interacts with TEAD to regulate the transcription of its target gene connective tissue growth factor (CTGF), thus leading to the occurrence of tumors (Anna et al 2016;Kang et al, 2018;Zhou et al, 2020). CTGF is a key factor in renal fibrosis (Toda et al, 2018), and whether YAP1 can also promote the transcription of CTGF during the pathogenesis of renal interstitial fibrosis has not been reported.…”

Silencing of lncRNA MIR497HG via CRISPR/Cas13d Induces Bladder Cancer Progression Through Promoting the Crosstalk Between Hippo/Yap and TGF-β/Smad Signaling

“…Moreover, we found that miR-195/497 cluster decreased the formation of regulatory transcription complex containing Yap and Smad3, while decreasing their common target genes, such as the gene-encoding CTGF ( Luo, 2017 ). Various studies have revealed that CTGF is critical in cancer progression and initiation ( Chen et al, 2019 ; Pu et al, 2019 ; Zhou et al, 2020 ).…”

Angiomotin‐like 1 plays a tumor‐promoting role in glioma by enhancing the activation of YAP1 signaling

“…13 In gastric cancer cells, AMOTL1 knockdown not only reduces cellular proliferation and invasion but also induces cell cycle arrest and cell apoptosis. 12 These findings collectively suggest that AMOTL1 has a cancer-promoting role. In line with these studies, our results showed that silencing AMOTL1 impeded and AMOTL1 overexpression enhanced glioma cell proliferation and invasion.…”