Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation

Abstract

The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation.

Crosstalk of Cancer Signaling Pathways by Cyclic Hexapeptides and Anthraquinones from Rubia cordifolia

“…Recently, another molecular mechanism of compound 6 has been proposed by Ji et al [ 30 ]. Compound 6 isolated from Bourvardia ternifolia has been shown to control tumor growth via the inhibition of YAP/TAZ activation.…”

“…Compound 6 isolated from Bourvardia ternifolia has been shown to control tumor growth via the inhibition of YAP/TAZ activation. The yes-associated protein (YAP) and its paralog, PSD-95/Dlg/ZO-1 binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway and genetic inactivation of YAP could be an effective target to inhibit tumorigenesis [ 30 ]. Hippo signaling is an evolutionarily conserved pathway that controls organ growth by regulating cell proliferation, apoptosis, stem cell self-renewal, and dysregulation of this pathway contributes to the cancer development [ 31 ].…”

CCN2 (Cellular Communication Network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis

“…Targeting CCN2 may be a therapeutic option for diseases associated with increased CCN2 expression, malignant as well as non-malignant. CCN2 can be inhibited by: The use of an anti-CCN2 antibody (Aikawa et al 2006 ; Alapati et al 2011 ; Barbe et al 2020a , b ; Bickelhaupt et al 2017 ; Dornhofer et al 2006 ; Finger et al 2014 ; Makino et al 2017 ; Moran-Jones et al 2015 ; Neesse et al 2013 ; Ohara et al 2018 ; Raghu et al 2016 ; Richeldi et al 2020 ; Sakai et al 2017 ), Gene expression silencing by antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) (Chen et al 2014 ; Gale et al 2018 ; Gibson et al 2017 ; Jensen et al 2018 ; Kang et al 2020 ; Li et al 2006 ; Okada et al 2005 ; Sisco et al 2008 ; Sung et al 2013 ; Yokoi et al 2004 ; Yoon et al 2016 ), Drugs that indirectly (and less specifically) inhibit CCN2 expression, for example by targeting Sirtuin 1 (Sirt1) (Ren et al 2017 ), peroxisome proliferator-activated receptor gamma (PPARγ) (Sun et al 2006 ; Zhao et al 2006 ), the CCN2 transcriptional regulators YAP and TAZ (Ji et al 2018 ), or proteins involved in signaling pathways affecting CCN2 transcription such FAK (Peidl et al 2019 ), The use of CCN3, as it can antagonize the effects of CCN2 (Peidl et al 2019 ; Riser et al 2009 , 2010 , 2014 ). Of the above, only the use of an anti-CCN2 antibody and the use of ASOs and siRNAs have made it to clinical trials for their direct effect on CCN2 (Gale et al 2018 ; Jensen et al 2018 ; https://www.prnewswire.com/news-releases/rxi-pharmaceuticals-announces-positive-results-from-phase-12-trial-with-rxi-109-for-retinal-scarring-300690078.html ; http://www.sc...…”

“…Drugs that indirectly (and less specifically) inhibit CCN2 expression, for example by targeting Sirtuin 1 (Sirt1) (Ren et al 2017 ), peroxisome proliferator-activated receptor gamma (PPARγ) (Sun et al 2006 ; Zhao et al 2006 ), the CCN2 transcriptional regulators YAP and TAZ (Ji et al 2018 ), or proteins involved in signaling pathways affecting CCN2 transcription such FAK (Peidl et al 2019 ),…”

“…Gene expression silencing by antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) (Chen et al 2014;Gale et al 2018;Gibson et al 2017;Jensen et al 2018;Kang et al 2020;Li et al 2006;Okada et al 2005;Sisco et al 2008;Sung et al 2013;Yokoi et al 2004;Yoon et al 2016), 3. Drugs that indirectly (and less specifically) inhibit CCN2 expression, for example by targeting Sirtuin 1 (Sirt1) (Ren et al 2017), peroxisome proliferator-activated receptor gamma (PPARγ) (Sun et al 2006;Zhao et al 2006), the CCN2 transcriptional regulators YAP and TAZ (Ji et al 2018), or proteins involved in signaling pathways affecting CCN2 transcription such FAK (Peidl et al 2019), 4. The use of CCN3, as it can antagonize the effects of CCN2 (Peidl et al 2019;Riser et al 2009Riser et al , 2010Riser et al , 2014).…”