The Role of Hippo Pathway in Cancer Stem Cell Biology

Abstract

The biological significance and deregulation of the Hippo pathway during organ growth and tumorigenesis have received a surge of interest in the past decade. The Hippo pathway core kinases, MST1/2 and LATS1/2, are tumor suppressors that inhibit the oncogenic nuclear function of YAP/TAZ and TEAD. In addition to earlier studies that highlight the role of Hippo pathway in organ size control, cell proliferation, and tumor development, recent evidence demonstrates its critical role in cancer stem cell biology, including EMT, drug resistance, and self-renewal. Here we provide a brief overview of the regulatory mechanisms of the Hippo pathway, its role in cancer stem cell biology, and promising therapeutic interventions.

Keywords: Hippo pathway; YAP/TAZ; cancer stem cell; metastasis.

Fig. 1. Regulation of YAP and TAZ by the Hippo pathway

The core inhibitory kinase module of the Hippo pathway is composed of MST1/2, MAP4K, and LATS1/2. The transcriptional module is composed of YAP/TAZ and TEAD. (A) When the Hippo pathway is ‘off’, YAP/TAZ are dephosphorylated, accumulated, and they translocate into the nucleus to bind the transcription factors, TEAD1–TEAD4, which enable target gene transcription involved in cell proliferation. (B) When the Hippo pathway is turned ‘on’, LATS1/2 directly phosphorylate YAP/TAZ, which inhibit nuclear import of YAP/TAZ via 14-3-3-mediated cytoplasmic retention, and ubiquitination-mediated proteasomal and autolysosomal degradation. TEAD transcriptional activity is suppressed by VGLL4. LATS indicates large tumor suppressor; MST, mammalian STE20-like protein kinase; YAP, Yes-associated protein; TAZ, transcriptional co-activator with PDZ-binding motif; TEAD, TEA domain family members; VGLL4, transcription cofactor vestigial-like protein 4.

Fig. 2. Overview of YAP/TAZ regulation and function in cancer stem cells

The Hippo pathway regulates YAP/TAZ activation in cancer cells through a wide range of upstream stimuli, such as extracellular ligands, mechanotransduction, environmental stress, energy stress, and cell-cell contact. Aberrant activation of YAP/TAZ via dysregulation of the Hippo pathway results in tumorigenesis and confers cancer stem cell traits that lead to anoikis resistance, EMT, drug resistance, and metastasis.

Fig. 3. Therapeutic targeting of the Hippo pathway

Strategies for targeting Hippo-YAP/TAZ activity are indicated. Dasatinib, ROCK inhibitors, statins, GGTI (inhibitors of geranylgeranyl transferase-1) represent compounds that inhibit YAP/TAZ activity via activating LATS. Rapamycin, tankyrase inhibitors, metformin, 2-DG represent compounds that inhibit YAP/TAZ activity independent of LATS. Verteporfin and VGLL4-mimicking peptide represent compounds that inhibit the interaction between YAP/TAZ and TEAD. ROCK indicates Rho-associated protein kinase; FAK, focal adhesion kinase; PKA, protein kinase A; APC, adenomatous polyposis coli; AMPK, AMP-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; RTK, receptor tyrosine kinase; GPCR, G-protein coupled receptor.