Oxidative stress-CBP axis modulates MOB1 acetylation and activates the Hippo signaling pathway

Reactive oxygen species (ROS) are constantly produced in cells, an excess of which causes oxidative stress. ROS has been linked to regulation of the Hippo pathway; however, the underlying detailed mechanisms remain unclear. Here, we report that MOB1, a substrate of MST1/2 and co-activator of LATS1/2 in the canonical Hippo pathway, interacts with and is acetylated at lysine 11 by acetyltransferase CBP and deacetylated by HDAC6. MOB1-K11 acetylation stabilizes itself by reducing its binding capacity with E3 ligase Praja2 and subsequent ubiquitination. MOB1-K11 acetylation increases its phosphorylation and activates LATS1. Importantly, upstream oxidative stress signals promote MOB1 acetylation by suppressing CBP degradation, independent of MST1/2 kinase activity and HDAC6 deacetylation effect, thereby linking oxidative stress to activation of the Hippo pathway. Functionally, the acetylation-deficient mutant MOB1-K11R promotes lung cancer cell proliferation, migration and invasion in vitro and accelerates tumor growth in vivo, compared to the wild-type MOB1. Clinically, acetylated MOB1 corresponds to better prediction of overall survival in patients with non-small cell lung cancer. Therefore, as demonstrated, an oxidative stress-CBP regulatory axis controls MOB1-K11 acetylation and activates LATS1, thereby activating the Hippo pathway and suppressing YAP/TAZ nuclear translocation and tumor progression.     

Regulation of Hippo signaling pathway in cancer: A MicroRNA perspective

Recent studies have suggested that Hippo signaling is not only involved in controlling organ size in Drosophila but can also regulate cell proliferation, tissue homeostasis, differentiation, apoptosis and regeneration. Any dysregulation of Hippo signaling, especially the hyper activation of its downstream effectors YAP/TAZ, can lead to uncontrolled cell proliferation and malignant transformation. In majority of cancers, expression of YAP/TAZ is extremely high and this increased expression of YAP/TAZ has been shown to be an independent predictor of prognosis and indicator of increased cell proliferation, metastasis and poor survival. In this review, we have summarized the most recent findings about the cross talk of Hippo signaling pathway with other signaling pathways and its regulation by different miRNAs in various cancer types. Recent evidence has suggested that Hippo pathway is also involved in mediating the resistance of different cancer cells to chemotherapeutic drugs and in a few cancer types, this is brought about by regulating miRNAs. Therefore, the delineation of the underlying mechanisms regulating the chemotherapeutic resistance might help in developing better treatment options. This review has attempted to provide an overview of different drugs/options which can be utilized to target oncogenic YAP/TAZ proteins for therapeutic interventions.     

YAP‐TEAD signaling promotes basal cell carcinoma development via a c‐JUN/AP1 axis

The mammalian Hippo signaling pathway, through its effectors YAP and TAZ, coerces epithelial progenitor cell expansion for appropriate tissue development or regeneration upon damage. Its ability to drive rapid tissue growth explains why many oncogenic events frequently exploit this pathway to promote cancer phenotypes. Indeed, several tumor types including basal cell carcinoma (BCC) show genetic aberrations in the Hippo (or YAP/TAZ) regulators. Here, we uncover that while YAP is dispensable for homeostatic epidermal regeneration, it is required for BCC development. Our clonal analyses further demonstrate that the few emerging Yap‐null dysplasia have lower fitness and thus are diminished as they progress to invasive BCC. Mechanistically, YAP depletion in BCC tumors leads to effective impairment of the JNK‐JUN signaling, a well‐established tumor‐driving cascade. Importantly, in this context, YAP does not influence canonical Wnt or Hedgehog signaling. Overall, we reveal Hippo signaling as an independent promoter of BCC pathogenesis and thereby a viable target for drug‐resistant BCC.     

MEK1 promotes YAP and their interaction is critical for tumorigenesis in liver cancer

Mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1) as well as Yes-associated protein (YAP), the downstream effector of Hippo signaling pathway, is linked to hepatocarcinogenesis. However, little is known about whether and how MEK1 interacts with YAP. In this study, we find that MEK1-YAP interaction is critical for liver cancer cell proliferation and maintenance of transformed phenotypes both in vitro and in vivo. Moreover, MEK1 and YAP proteins are closely correlated in human liver cancer samples. Mechanistically, inhibition of MEK1 by both PD98059 and U0126 as well as RNAi reduces beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC), which acts as a potential endogenous YAP protector.     

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

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.