Targeting the Hippo/YAP/TAZ signalling pathway: Novel opportunities for therapeutic interventions into skin cancers

\ua9 2022 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.Skin cancers are by far the most frequently diagnosed human cancers. The closely related transcriptional co-regulator proteins YAP and TAZ (WWTR1) have emerged as important drivers of tumour initiation, progression and metastasis in melanoma and non-melanoma skin cancers. YAP/TAZ serve as an essential signalling hub by integrating signals from multiple upstream pathways. In this review, we summarize the roles of YAP/TAZ in skin physiology and tumorigenesis and discuss recent efforts of therapeutic interventions that target YAP/TAZ in in both preclinical and clinical settings, as well as their prospects for use as skin cancer treatments

The Hippo Pathway in Prostate Cancer

Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors—the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)—are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa

O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MST-LATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.ope

Roles for Hippo pathway effectors Taz and Yap in cancer and fibrosis

The Hippo pathway is a well-conserved signaling pathway composed of a series of kinases, ending in the LATS1 and LATS2 kinases (LATS1/2), that control the activity of the transcriptional effectors TAZ and YAP (TAZ/YAP). The Hippo pathway is responsive to several external cues, including mechanical stiffness and cell-cell contact. The transcriptional targets of TAZ/YAP have a wide range of effects, including promotion of cell growth, inhibition of apoptosis, regulation of cell fate, and secretion of growth factors. Due to their wide-ranging effects, in these studies we investigated the roles for TAZ and YAP in several disease areas. First, we explored the roles of TAZ/YAP in glutamine addiction, a phenomenon in which cancer cells rely on glutamine for cell growth, in breast cancer. We demonstrated that breast cancer cells with high TAZ/YAP expression exhibit more reliance on glutamine as an energy source than those with low TAZ/YAP. Depletion of TAZ/YAP in high-TAZ/YAP breast cancer cell lines reduced their reliance on glutamine. We showed that TAZ/YAP promote increased transcription of the transaminases GOT1 and PSAT1, which allow for the carbon from glutamine to enter the tricarboxylic acid cycle and generate energy, providing a mechanism by which TAZ/YAP allow for increased processing of glutamine. Second, we explored whether and how loss of Hippo pathway activity contributes to the formation of melanoma. The most common genetic mutation found in melanoma patients is BrafV600E, but this mutation alone is insufficient to drive melanomagenesis, instead promoting an initial proliferative burst that ends in senescence. We found that BrafV600E activates the Hippo pathway to inhibit TAZ/YAP, contributing to the observed growth arrest phenotype in precancerous nevi. We found that deletion of Lats1/2 in melanocytes alone or in combination with BrafV600E expression lead to the rapid development of melanoma in mice. Third, we assessed how TAZ/YAP mediate homeostasis, injury response, and fibrosis in the lung. We explored TAZ/YAP responses in tissue regeneration and fibrosis using the bleomycin injury model in mice. We found that nuclear levels of TAZ/YAP dynamically increase in the epithelium and mesenchyme of the lung after injury; nuclear TAZ/YAP decreases in these populations as the injury resolves. We conditionally deleted Taz and/or Yap in a subset of mesenchymal cells marked by Platelet-Derived Growth Factor Receptor β (PDGFRβ) in adult mice and found that TAZ and YAP play essential roles in lung homeostasis and responses to bleomycin-injury, with TAZ/YAP-deleted animals showing reduced survival. Notable defects included disorganization of lung epithelial and endothelial cells, indicating that TAZ/YAP in PDGFRβ-expressing cells direct signals that coordinate cellular homeostasis in the lung. In total, these studies detail new mechanisms for TAZ/YAP and Hippo signaling in lung homeostasis and injury repair, melanoma development, and metabolic reprogramming in breast cancer

YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis

Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1-induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP-induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding

YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis

Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1-induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP-induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding

Removal of antagonistic spindle forces can rescue metaphase spindle length and reduce chromosome segregation defects

Regular Abstracts - Tuesday Poster Presentations: no. 1925Metaphase describes a phase of mitosis where chromosomes are attached and oriented on the bipolar spindle for subsequent segregation at anaphase. In diverse cell types, the metaphase spindle is maintained at a relatively constant length. Metaphase spindle length is proposed to be regulated by a balance of pushing and pulling forces generated by distinct sets of spindle microtubules and their interactions with motors and microtubule-associated proteins (MAPs). Spindle length appears important for chromosome segregation fidelity, as cells with shorter or longer than normal metaphase spindles, generated through deletion or inhibition of individual mitotic motors or MAPs, showed chromosome segregation defects. To test the force balance model of spindle length control and its effect on chromosome segregation, we applied fast microfluidic temperature-control with live-cell imaging to monitor the effect of switching off different combinations of antagonistic forces in the fission yeast metaphase spindle. We show that spindle midzone proteins kinesin-5 cut7p and microtubule bundler ase1p contribute to outward pushing forces, and spindle kinetochore proteins kinesin-8 klp5/6p and dam1p contribute to inward pulling forces. Removing these proteins individually led to aberrant metaphase spindle length and chromosome segregation defects. Removing these proteins in antagonistic combination rescued the defective spindle length and, in some combinations, also partially rescued chromosome segregation defects. Our results stress the importance of proper chromosome-to-microtubule attachment over spindle length regulation for proper chromosome segregation.postprin

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin

The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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