Wnt/β-catenin signaling: components, mechanisms, and diseases

Since the initial discovery of the oncogenic activity of WNT1 in mouse mammary glands, our appreciation for the complex roles for WNT signalling pathways in cancer has increased dramatically. WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis. Although WNT signalling pathways have been difficult to target, improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models, thus setting the stage for clinical trials in humans.

WNT signalling pathways as therapeutic targets in cancer

The Wnt signalling pathway is an ancient system that has been highly conserved during evolution. It has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms and in many other processes. Mutations or deregulated expression of components of the Wnt pathway can induce disease, most importantly cancer. The first gene to be identified that encodes a Wnt signalling component, Int1 (integration 1), was molecularly characterized from mouse tumour cells 25 years ago. In parallel, the homologous gene Wingless in Drosophila melanogaster, which produces developmental defects in embryos, was characterized. Since then, further components of the Wnt pathway have been identified and their epistatic relationships have been defined. This article is a Timeline of crucial discoveries about the components and functions of this essential pathway.

Wnt signalling and its impact on development and cancer

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. CSCs use many of the same signaling pathways that are found in normal stem cells, such as Wnt, Notch, and Hedgehog (Hh). The origin of CSCs is not fully understood, but data suggest that they originate from normal stem or progenitor cells, or possibly other cancer cells. Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. Development of agents that target critical steps in the Wnt, Notch, and Hh pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are described in this Review.

Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways

The Wnt signaling pathways are involved in embryo development as well as in tumorigenesis. Dishevelled (Dvl) transduces Wnt signals from the receptor Frizzled (Fz) to downstream components in canonical and noncanonical Wnt signaling pathways. The Dvl PDZ domain is thought to play an essential role in both pathways, and we recently demonstrated that the Dvl PDZ domain binds directly to Fz receptors. In this study, using structure-based virtual ligand screening, we identified an organic molecule (NSC668036) from the National Cancer Institute small-molecule library that can bind to the Dvl PDZ domain. We then used molecular dynamics simulation to analyze the binding between the PDZ domain and NSC668036 in detail. In addition, we showed that, in Xenopus, as expected, NSC668036 inhibited the signaling induced by Wnt3A. This compound provides a basis for rational design of high-affinity inhibitors of the PDZ domain, which can block Wnt signaling by interrupting the Fz-Dvl interaction.

Identification of a specific inhibitor of the Dishevelled PDZ domain

Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled

/pdf/planar-cell-polarity-regulators-in-asymmetric-organogenesis-jhuspwov.pdf

Planar cell polarity regulators in asymmetric organogenesis during development and disease.

Simple Summary RBM24 is a highly conserved RNA-binding protein that plays critical roles in the post-transcriptional regulation of gene expression for initiating cell differentiation during embryonic development and for maintaining tissue homeostasis in adult life. Evidence is now accumulating that it is frequently dysregulated across human cancers. Importantly, RBM24 may act as a tumor suppressor or as an oncogene in a context- or background-dependent manner. Its activity can be regulated by protein–protein interactions and post-translational modifications, making it a potential therapeutic target for cancer treatment. However, molecular mechanisms underlying its function in tumor growth and metastasis remain elusive. Further investigation will be necessary to better understand how its post-transcriptional regulatory activity is controlled and how it is implicated in tumor progression. This review provides a comprehensive analysis of recent findings on the implication of RBM24 in cancer and proposes future research directions to delve more deeply into the mechanisms underlying its tumor-suppressive function or oncogenic activity. Abstract RNA-binding proteins are critical post-transcriptional regulators of gene expression. They are implicated in a wide range of physiological and pathological processes by modulating nearly every aspect of RNA metabolisms. Alterations in their expression and function disrupt tissue homeostasis and lead to the occurrence of various cancers. RBM24 is a highly conserved protein that binds to a large spectrum of target mRNAs and regulates many post-transcriptional events ranging from pre-mRNA splicing to mRNA stability, polyadenylation and translation. Studies using different animal models indicate that it plays an essential role in promoting cellular differentiation during organogenesis and tissue regeneration. Evidence is also accumulating that its dysregulation frequently occurs across human cancers. In several tissues, RBM24 clearly functions as a tumor suppressor, which is consistent with its inhibitory potential on cell proliferation. However, upregulation of RBM24 in other cancers appears to promote tumor growth. There is a possibility that RBM24 displays both anti-tumor and pro-tumor activities, which may be regulated in part through differential interactions with its protein partners and by its post-translational modifications. This makes it a potential biomarker for diagnosis and prognosis, as well as a therapeutic target for cancer treatment. The challenge remains to determine the post-transcriptional mechanisms by which RBM24 modulates gene expression and tumor progression in a context- or background-dependent manner. This review discusses recent findings on the potential function of RBM24 in tumorigenesis and provides future directions for better understanding its regulatory role in cancer cells.

/pdf/rbm24-in-the-post-transcriptional-regulation-of-cancer-3avo6197.pdf

RBM24 in the Post-Transcriptional Regulation of Cancer Progression: Anti-Tumor or Pro-Tumor Activity?

RNA-binding proteins (RBPs) regulate gene expression at the post-transcriptional level. They play major roles in the tissue- and stage-specific expression of protein isoforms as well as in the maintenance of protein homeostasis. The inner ear is a bi-functional organ, with the cochlea and the vestibular system required for hearing and for maintaining balance, respectively. It is relatively well documented that transcription factors and signaling pathways are critically involved in the formation of inner ear structures and in the development of hair cells. Accumulating evidence highlights emerging functions of RBPs in the post-transcriptional regulation of inner ear development and hair cell function. Importantly, mutations of splicing factors of the RBP family and defective alternative splicing, which result in inappropriate expression of protein isoforms, lead to deafness in both animal models and humans. Because RBPs are critical regulators of cell proliferation and differentiation, they present the potential to promote hair cell regeneration following noise- or ototoxin-induced damage through mitotic and non-mitotic mechanisms. Therefore, deciphering RBP-regulated events during inner ear development and hair cell regeneration can help define therapeutic strategies for treatment of hearing loss. In this review, we outline our evolving understanding of the implications of RBPs in hair cell formation and hearing disease with the aim of promoting future research in this field.

/pdf/emerging-roles-of-rna-binding-proteins-in-inner-ear-hair-clr6rajw.pdf

De Li Shi

Papers

Identification of a specific inhibitor of the Dishevelled PDZ domain

Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled

Planar cell polarity regulators in asymmetric organogenesis during development and disease.

RBM24 in the Post-Transcriptional Regulation of Cancer Progression: Anti-Tumor or Pro-Tumor Activity?

Emerging Roles of RNA-Binding Proteins in Inner Ear Hair Cell Development and Regeneration