Inhibition of YAP suppresses CML cell proliferation and enhances efficacy of imatinib in vitro and in vivo

Abstract

BackgroundYes-associated protein (YAP), an essential component of Hippo pathway, was identified as an oncoprotein which participated in the progression of various malignancies. However, its role in chronic myeloid leukemia (CML) remains to be further clarified.MethodsThe expression of YAP in CML cells was determined by western blotting. Next, the effects of YAP knockdown and YAP inhibitor on CML cells were evaluated by MTT assay, flow cytometry (FCM) and Wright’s staining. Moreover, K562 induced mice model was employed to further investigate the role of YAP in vivo.ResultsYAP was overexpressed in CML cells. Knockdown of YAP by si-RNA or inhibition the function of YAP using verteporfin (VP) not only inhibited the proliferation, induced the apoptosis of CML cells but also reduced the expression of YAP target genes c-myc and survivin. Additionally, VP enhanced the efficacy of imatinib (IM) in vitro and suppressed leukemogenesis in vivo.ConclusionOur results indicate that YAP may play an important role in the proliferation and leukemogenesis of CML cells. Genetic or pharmacological inhibition of YAP provides a novel treatment strategy for CML.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0414-z) contains supplementary material, which is available to authorized users.

Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Human Leukemia NB4 Cells without Light Activation

“…These results suggest that VP suppresses NB4 cell proliferation. Interestingly, VP has been reported to inhibit cell proliferation and to induce G0/G1 arrest in pancreatic ductal adenocarcinoma cells, hepatocellular carcinoma cells, human retinoblastoma cells, uveal melanoma cells, and chronic granulocyte leukemia cells 20 , 22 , 27 - 29 . Similarly, our FCM data also indicate that cell cycle arrest at the G0/G1 phase is induced by VP treatment.…”

Effect of YAP Inhibition on Human Leukemia HL-60 Cells

“…Therefore, novel therapeutic targets are necessary to improve the outcomes for patients with APL 27 . YAP functions as an oncoprotein by interacting with TEAD, forming a protein complex critical for the transcription of downstream genes such as c-Myc and Survivin 15 , 22 . Recently, porphyrin family members including VP, hematoporphyrin, and protoporphyrin IX have been found to abrogate the interaction between YAP and TEAD and found function as YAP inhibitors 25 , 28 .…”

“…Recently, porphyrin family members including VP, hematoporphyrin, and protoporphyrin IX have been found to abrogate the interaction between YAP and TEAD and found function as YAP inhibitors 25 , 28 . However, while MST1/2 and YAP1 gene expression have been analyzed in AML 29 , and inhibition of YAP results in a significant anti-leukemia effect in chronic myeloid leukemia 15 , the effect of YAP inhibition in APL remains unclear. Here, we demonstrate the effects of YAP knockdown and the inhibition of YAP function by shRNA and VP, respectively, in HL-60 cells.…”

“…Additionally, YAP amplification and overexpression have been observed in various human cancers, including pancreatic cancer, renal cell carcinoma, breast cancer, cholangiocarcinoma, and medulloblastoma 14 , 19 - 22 . Moreover, YAP expression is significantly higher in patients with leukemia, including chronic lymphoblastic leukemia, and chronic myeloid leukemia than in healthy donors 15 , 23 . Furthermore, it has been suggested that YAP may be a target for regenerative medicine and cancer treatment 24 .…”

Transcriptional co-activator YAP regulates cAMP signaling in Sertoli cells

“…However, recent studies have shown that verteporfin without light activation inactivates YAP by inducing conformational changes in YAP protein and enhancing its cytoplasmic retention (Liu-Chittenden et al, 2012;Wang et al, 2016). A number of studies have demonstrated the efficacy of verteporfin as a potent YAP inhibitor and its therapeutic potential for treatment of cancer (Chen et al, 2015;He et al, 2015;Hsu et al, n.d.;Li et al, 2016;Yu et al, 2014). In our study, we treated Sc with verteporfin and analyzed the mRNA levels of a number of genes that are characteristic of functionally mature Sc.…”