C-MYC and BCL-2 mediate YAP-regulated tumorigenesis in OSCC

Abstract

Transcriptional co-activator Yes-associated protein (YAP) is a key oncogene in mammalian cells. The present understanding of YAP in oral squamous cells carcinoma (OSCC) remains unclear. The purpose of this study is to investigate the effects of YAP on proliferation and apoptosis in OSCC and the molecular mechanism. The results showed the expression level of YAP was higher in OSCC tissues than that in adjacent normal tissues. Knockdown of YAP in CAL27 cell lines prohibited cell proliferation while augmented apoptosis. Conversely, overexpression of YAP protected cells from apoptosis and promoted cell proliferation. Moreover, C-MYC and BCL-2 mRNA and protein levels were altered due to the differential expression of YAP. Subsequent Verteporfin treatment in CAL27 cells revealed that the transcription and translation of BCL-2 and C-MYC both decreased. In a tumor xenograft model, knockdown of YAP suppressed tumor growth of CAL27 in vivo, while YAP overexpression promoted the tumor growth. These results suggest that YAP is a crucial regulator that exerts pro-proliferation and anti-apoptosis effects in OSCC through actions affecting the cell cycle and intrinsic apoptotic signaling. Thus YAP could potentially serve as a valuable molecular biomarker or therapeutic target in the treatment of OSCC.

<p>Melatonin Regulates Cisplatin Resistance and Glucose Metabolism Through Hippo Signaling in Hepatocellular Carcinoma Cells</p>

“…Bcl-2 was identified as a YAP downstream protein. 47 In our work, YAP depletion downregulated Bcl-2 protein expression as a similar effect as MEL treatment mediated. Notably, YAP overexpression partially restored cell viability and reduced cisplatin-induced apoptosis.…”

“…Overexpression of YAP was detected in several cancers 46 and enabled to aid cell cycle progression via inducing cyclin proteins' expression and inhibiting p21. 47,48 In the present study, YAP silencing caused a reduced expression of Bcl-2 and GLUT-3, while its overexpression counteracted the MEL suppressive properties on HCC cells, indicating that MEL inhibited HCC growth partly through its inhibiting effect on YAP.…”

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

“…Originally, verteporfin was defined as a clinical photosensitizer and is an inhibitor of the YAP‐TEAD interaction . In previous reports, verteporfin without light activation was reported to exhibit cytotoxicity while suppressing the YAP pathway at a concentration of approximately 2–20 μ m (10–100 times higher than the concentration used in the current study) . In the present study, siRNA‐mediated knockdown of YAP did not reduce the MMP in GSCs, whereas verteporfin led to a reduction in the YAP‐knocked down GSCs.…”

“…We therefore screened drugs in clinical use for their ability to reduce MMP as an indicator and identified verteporfin (VPF, trade name Visudyne ® ), a Food and Drug Administration‐approved photoactivating drug that is used clinically for macular degeneration, as a candidate drug for targeting the OXPHOS in GSCs . Indeed, it has been reported that VPF suppresses cell proliferation and induces cell death of various cancer cells including glioblastoma cells as its side effect so far, but there is no report in GSCs . The medical effect of verteporfin is photoactivation‐dependent .…”

Yes-associated protein (YAP) is required in maintaining normal ovarian follicle development and function

“…Cyclin intracellular concentrations are regulated by mitogenic signals such as Ras/MAP kinases, as well as Phosphoinositide 3-kinase. In the bladder [36], Oral squamous [37], gastric [38] cancer cells nuclear YAP leads to the upregulation of Cyclin D1, promoting cell proliferation. In ovarian granulosa cells, cyclin D2 is induced and under the control of FSH signaling, via a cyclic-AMP-dependent pathway [39].…”