Molecular Pathways: Hippo Signaling, a Critical Tumor Suppressor

Abstract

The Salvador-Warts-Hippo pathway controls cell fate and tissue growth. The main function of the Hippo pathway is to prevent YAP and TAZ translocation to the nucleus where they induce the transcription of genes involved in cell proliferation, survival, and stem cell maintenance. Hippo signaling is thus a complex tumor suppressor, and its deregulation is a key feature in many cancers. Recent mounting evidence suggests that the overexpression of Hippo components can be useful prognostic biomarkers. Moreover, Hippo signaling appears to be intimately linked to some of the most important signaling pathways involved in cancer development and progression. A better understanding of the Hippo pathway is thus essential to untangle tumor biology and to develop novel anticancer therapies. Here, we comment on the progress made in understanding Hippo signaling and its connections, and also on how new drugs modulating this pathway, such as Verteporfin and C19, are highly promising cancer therapeutics.

Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP‐TEAD complex

“…Hippo signaling is also involved in tumor progression, metastasis, and angiogenesis . In cholangiocarcinoma, hyperactivated YAP enhanced the expression of pro‐angiogenic MFAP5 .…”

“…Recent studies suggest that the Hippo-YAP pathway is implicated in cell proliferation, apoptosis, chemo-resistance and angiogenesis. (6,37) YAP regulates the transcription of cyclinD1 and FOXM1, which are important factors for G1 progression and G1/S transition. (31) Hyperactivated YAP also regulates the insensitivity to apoptosis of cancer cells.…”

“…The Yes‐associated protein 1 (YAP) is the most critical downstream effector in the Hippo signaling cascade, and plays an essential role in physiological and pathological process . YAP serves as a transcriptional co‐activator and regulates the activity of various transcription factors, such as TEADs and CTGF, which are implicated in cell proliferation, apoptosis, chemoresistance and angiogenesis . YAP is highly expressed in several types of malignant tumors including pancreatic cancer, and is shown to participate in the development, progression and recurrence of PDAC .…”

“…(5) YAP serves as a transcriptional co-activator and regulates the activity of various transcription factors, such as TEADs and CTGF, which are implicated in cell proliferation, apoptosis, chemoresistance and angiogenesis. (6) YAP is highly expressed in several types of malignant tumors including pancreatic cancer, (7)(8)(9) and is shown to participate in the development, progression and recurrence of PDAC. (10,11) Hyperactivated YAP could enhance the secretion of microfibrillar associated protein 5 (MFAP5) to promote neoangiogenesis in vitro and in vivo.…”

A genetic variant in Rassf1a predicts outcome in mCRC patients treated with cetuximab plus chemotherapy: results from FIRE-3 and JACCRO 05 and 06 trials

“…In recent times, several studies have highlighted the implication of deregulated Hippo signaling in cancer development and progression 1 . This novel pathway acts as a complex tumor suppressor network controlling cell growth, proliferation, stem-cell maintenance and epithelium mesenchymal transition 2 . Hippo’s signaling core consists of a complex of kinases whose activation ultimately leads to the phosphorylation of the oncoproteins YAP and TAZ preventing their translocation to the nucleus.…”