miR-195-5p as Regulator of γ-Catenin and Desmosome Junctions in Colorectal Cancer.

Desmosomes play a key role in the regulation of cell adhesion and signaling. Dysregulation of the desmosome complex is associated with the loss of epithelial cell polarity and disorganized tissue architecture typical of colorectal cancer (CRC). The aim of this study was to investigate and characterize the effect of miR-195-5p on desmosomal junction regulation in CRC. In detail, we proposed to investigate the deregulation of miR-195-5p and JUP, a gene target that encodes a desmosome component in CRC patients. JUP closely interacts with desmosomal cadherins, and downstream, it regulates several intracellular transduction factors. We restored the miR-195-5p levels by transient transfection in colonic epithelial cells to examine the effects of miR-195-5p on JUP mRNA and protein expression. The JUP regulation by miR-195-5p, in turn, determined a modulation of desmosome cadherins (Desmoglein 2 and Desmocollin 2). Furthermore, we focused on whether the miR-195-5p gain of function was also able to modulate the expression of key components of Wnt signaling, such as NLK, LEF1 and Cyclin D1. In conclusion, we have identified a novel mechanism controlled by miR-195-5p in the regulation of adhesive junctions, suggesting its potential clinical relevance for future miRNA-based therapy in CRC.

Downregulation of γ-Catenin by miR-195-5p Inhibits Colon Cancer Progression, Regulating Desmosome Function.

Desmosomes are essential structures for ensuring tissue functions, and their deregulation is involved in the development of colorectal cancer (CRC). JUP (γ-catenin) is a desmosome adhesion component that also acts as a signaling hub, suggesting its potential involvement in CRC progression. In this context, we recently demonstrated that miR-195-5p regulated JUP and desmosome cadherins expression. In addition, miR-195-5p gain of function indirectly modulated the expression of key effectors of the Wnt pathway involved in JUP-dependent signaling. Here, our purpose was to demonstrate the aberrant expression of miR-195-5p and JUP in CRC patients and to functionally characterize the role of miR-195-5p in the regulation of desmosome function. First, we showed that miR-195-5p was downregulated in CRC tumors compared to adjacent normal tissue. Then, we demonstrated that JUP expression was significantly increased in CRC tissues compared to adjacent normal tissues. The effects of miR-195-5p on CRC progression were assessed using in vitro transient transfection experiments and in vivo miRNA administration. Increased miR-195-5p in colonic epithelial cells strongly inhibits cell proliferation, viability, and invasion via JUP. In vivo gain of function of miR-195-5p reduced the numbers and sizes of tumors and significantly ameliorated the histopathological changes typical of CRC. In conclusion, our findings indicate a potential pharmacological target based on miR-195-5p replacement as a new therapeutic approach in CRC.

KRT13 promotes stemness and drives metastasis in breast cancer through a plakoglobin/c-Myc signaling pathway.

BACKGROUND: Keratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades. Keratin 13 (KRT13) plays an important role in breast cancer progression and metastasis. The objective of this study is to elucidate the mechanism by which KRT13 promotes breast cancer growth and metastasis. METHODS: The function and mechanisms of KRT13 in breast cancer progression and metastasis were assessed by overexpression and knockdown followed by examination of altered behaviors in breast cancer cells and in xenograft tumor formation in mouse mammary fat pad. Human breast cancer specimens were examined by immunohistochemistry and multiplexed quantum dot labeling analysis to correlate KRT13 expression to breast cancer progression and metastasis. RESULTS: KRT13-overexpressing MCF7 cells displayed increased proliferation, invasion, migration and in vivo tumor growth and metastasis to bone and lung. Conversely, KRT13 knockdown inhibited the aggressive behaviors of HCC1954 cells. At the molecular level, KRT13 directly interacted with plakoglobin (PG, γ-catenin) to form complexes with desmoplakin (DSP). This complex interfered with PG expression and nuclear translocation and abrogated PG-mediated suppression of c-Myc expression, while the KRT13/PG/c-Myc signaling pathway increased epithelial to mesenchymal transition and stem cell-like phenotype. KRT13 expression in 58 human breast cancer tissues was up-regulated especially at the invasive front and in metastatic specimens (12/18) (p < 0.05). KRT13 up-regulation in primary breast cancer was associated with decreased overall patient survival. CONCLUSIONS: This study reveals that KRT13 promotes breast cancer cell growth and metastasis via a plakoglobin/c-Myc pathway. Our findings reveal a potential novel pathway for therapeutic targeting of breast cancer progression and metastasis.

Overexpression of miRNA-9 enhances galectin-3 levels in oral cavity cancers.

Oral cavity cancer (OCC) is the predominant subtype of head and neck cancer (HNC) and has up to 50% mortality. Genome-wide microRNA (miR) sequencing data indicates overexpression of miR-9-5p in HNC tumours, however, the biological role of miR-9-5p in OCC is complex; it can either act as a tumour suppressor or an oncomir, regulating many target genes at the post-transcriptional level. We have investigated the overexpression of miR-9-5p in three OCC cell lines. We have evaluated its expression levels and Galectin-3 as potential biomarkers in saliva samples collected from controls and OCC patients. We found that over expression of miR-9-5p in OCC cell lines resulted in a significant reduction in cell proliferation and migration, and an increase in apoptosis, which was paralleled by an increase in Galectin-3 secretion and export of Galectin-3 protein. Our data are consistent with miR-9-5p being a modulator of Galectin-3 via the AKT/γ-catenin pathway. In addition, the positive correlation between the levels of miR-9-5p expression and secreted Galectin-3 in saliva reflects a similar relationship in vivo, and supports the utility of their integrative evaluation in OCC. Our findings indicate that both miR-9-5p and Galectin-3 are critical biomolecules in the progression of OCC.

TOPK promotes metastasis of esophageal squamous cell carcinoma by activating the Src/GSK3ß/STAT3 signaling pathway via γ-catenin.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a fatal disease with poor prognosis. The predominant reason for ESCC-related death is distal metastasis. A comprehensive understanding of the molecular mechanism underlying metastasis is needed for improving patient prognosis. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase, which plays a vital role in various physiological and pathophysiological processes. However, the role of TOPK in ESCC metastasis is unclear. METHODS: Tissue array was used to evaluate the correlation between TOPK expression and ESCC lymph node metastasis. Wound healing assay, transwell assay, and lung metastasis mice model were used to examine the role of TOPK in the migration of ESCC cells in vitro and in vivo. Protein kinase array, mass spectrometry (MS), and molecular modeling were used to examine the pathways and direct target proteins of TOPK that are involved in ESCC metastasis. Additionally, immunofluorescence and western blotting analyses were performed to verify these findings. RESULTS: The enhanced expression of TOPK was correlated with lymph node metastasis in the ESCC tissues. TOPK knockdown or treatment with the TOPK inhibitor (HI-TOPK-032) decreased the invasion and migration of ESCC cells in vitro. HI-TOPK-032 also inhibited the lung metastasis in ESCC cell xenograft in vivo model. Moreover, TOPK promoted the invasion of ESCC cells by activating the Src/GSK3ß/STAT3 and ERK signaling pathways via γ-catenin. CONCLUSION: The findings of this study reveal that TOPK is involved in ESCC metastasis and promoted the ESCC cell mobility by activating the Src/GSK3ß/STAT3 and ERK signaling pathways. This indicated that TOPK may be a potential molecular therapeutic target for ESCC metastasis.

FBW7 suppresses cell proliferation and G2/M cell cycle transition via promoting γ-catenin K63-linked ubiquitylation.

FBW7 is an E3 ubiquitin ligase and frequently mutated in various types of cancer. As a component of SCF ubiquitin ligase complex, FBW7 usually targets the substrates via K11 or K48-linked ubiquitylation and subsequent degradation of target proteins. Nevertheless, the role of FBW7 in mediating non-degradable ubiquitin signaling remains unknown in human cancers. In this study, we identified γ-catenin as a new binding protein of FBW7 by TAP-MS (tandem affinity purification-mass spectrum). Knockdown of FBW7 did not affect the stability of γ-catenin, but significantly reduced the K63-linked ubiquitin of γ-catenin, resulting in decreased expression of γ-catenin downstream gene 14-3-3σ. Rescue experiment revealed that γ-catenin promoted the expression of 14-3-3σ in a K63-linked ubiquitin signaling dependent manner. Furthermore, we showed that FBW7 cooperated with γ-catenin to inhibit G2/M cell cycle transition and cell proliferation. Taken together, our study uncovered a novel mechanism that FBW7 associated with γ-catenin and promoted its K63-linked ubiquitylation, providing new insights in understanding the role of FBW7 in inhibiting G2/M cell cycle transition and tumor cell proliferation.

MicroRNA-939 governs vascular integrity and angiogenesis through targeting γ-catenin in endothelial cells.

Coronary collateral circulation (CCC) functions as a natural bypass in the event of coronary obstruction, which markedly improves prognosis in patients with coronary artery disease (CAD). MicroRNAs (miRNAs) have been implicated in multiple physiological and pathological processes, including angiogenesis involved in CCC growth. The roles that miRNA-939 (miR-939) plays in angiogenesis remain largely unknown. We conducted this study to explore the expression of miR-939 in CAD patients and its role in angiogenesis. For the first time, our results indicated that the expression of circulating miR-939 was down-regulated in patients with sufficient CCC compared with patients with poor CCC. Overexpression of miR-939 in primary human umbilical vein endothelial cells (HUVECs) significantly inhibited the proliferation, adhesion and tube formation, but promoted the migration of cells. In contrast, miR-939 knockdown exerted reverse effects. We further identified that γ-catenin was a novel target of miR-939 by translational repression, which could rescue the effects of miR-939 in HUVECs. In summary, this study revealed that the expression of circulating miR-939 was down-regulated in CAD patients with sufficient CCC. MiR-939 abolished vascular integrity and repressed angiogenesis through directly targeting γ-catenin. It provided a potential biomarker and a therapeutic target for CAD.

γ-Catenin acts as a tumor suppressor through context-dependent mechanisms in colorectal cancer.

PURPOSE: γ-Catenin is a protein closely related to ß-catenin. While the overexpression of ß-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells. METHODS: γ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model. RESULTS: γ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule ß-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo. CONCLUSIONS: This is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.

An EMMPRIN-γ-catenin-Nm23 complex drives ATP production and actomyosin contractility at endothelial junctions.

Cell-cell adhesions are important sites through which cells experience and resist forces. In endothelial cells, these forces regulate junction dynamics and determine endothelial barrier strength. We identify the Ig superfamily member EMMPRIN (also known as basigin) as a coordinator of forces at endothelial junctions. EMMPRIN localization at junctions correlates with endothelial junction strength in different mouse vascular beds. Accordingly, EMMPRIN-deficient mice show altered junctions and increased junction permeability. Lack of EMMPRIN alters the localization and function of VE-cadherin (also known as cadherin-5) by decreasing both actomyosin contractility and tugging forces at endothelial cell junctions. EMMPRIN ensures proper actomyosin-driven maturation of competent endothelial junctions by forming a molecular complex with γ-catenin (also known as junction plakoglobin) and Nm23 (also known as NME1), a nucleoside diphosphate kinase, thereby locally providing ATP to fuel the actomyosin machinery. These results provide a novel mechanism for the regulation of actomyosin contractility at endothelial junctions and might have broader implications in biological contexts such as angiogenesis, collective migration and tissue morphogenesis by coupling compartmentalized energy production to junction assembly.

Identification of HDAC4 as a target of γ-catenin that regulates the oncogenic K-Ras-mediated malignant phenotype of Rat2 cells.

The mechanisms by which activated Ras accelerates malignant transformation of normal cells are not fully understood. Here, we characterized the role and molecular mechanism of γ-catenin in regulating the malignant phenotype of Rat2 cells induced by codon 12-mutant K-Ras (K-Ras12V). Suppression of γ-catenin signaling by K-Ras12V was an early event and played a crucial role in promoting the acquisition of a highly metastatic phenotype of Rat2 cells. Notably, the gene encoding histone deacetylase 4 (HDAC4) was identified as a target of γ-catenin during this process. The transcription factor, lymphoid enhancer-binding factor-1 (Lef1), was involved in the modulation of HDAC4 transcription, and disruption of this pathway was a key event in promoting the invasion and migration of K-Ras12V-transduced Rat2 cells. Thus, our findings extend the range of targets for the development of new drugs for the therapy of oncogenic K-Ras-driven cancer.

DSC2 suppresses the growth of gastric cancer through the inhibition of nuclear translocation of γ-catenin and PTEN/PI3K/AKT signaling pathway.

BACKGROUND: Globally, gastric cancer (GC) is still a major leading cause of cancer-associated deaths. Downregulated desmocollin2 (DSC2) is considered to be closely related to tumor progression. However, the underlying mechanisms of DSC2 in GC progression require further exploration. METHOD: We initially constructed different GC cells based on DSC2 contents, established the mouse tumor xenografts, and subsequently performed clonal formation, MTT, Caspase-3 activity, and sperm DNA fragmentation assays to detect the functions of DSC2 in GC growth. Subsequently, we performed western blot, Co-IP, and immunofluorescence assays to investigate the underlying mechanisms through pretreatment with PI3K inhibitor, LY294002, and its activator, recombinant human insulin-like growth factor I (IGF1). RESULT: DSC2 could significantly inhibit the viability of GC cells at both in vitro and in vivo levels. The underlying mechanism may be that DSC2 binds the γ-catenin to decrease its nuclear level, thereby downregulating the anti-apoptotic factor BCL-2 expression and upregulating the pro-apoptotic factor P53 expression, which adjusts the PTEN/PI3K/AKT signaling pathway to promote the cancer cell apoptosis. CONCLUSIONS: Our finding suggests that DSC2 might be a potential therapeutic target for the treatment of cancers, most especially GC.

γ-Catenin Overexpression in AML Patients May Promote Tumor Cell Survival via Activation of the Wnt/ß-Catenin Axis.

BACKGROUND: Canonical Wnt/ß-catenin signaling is frequently dysregulated in acute myeloid leukemia (AML) and has been implicated in leukemogenesis. γ-catenin was previously demonstrated to be associated with the nuclear localization of ß-catenin, the central mediator, and to exert oncogenic effects in AML; however, the underlying mechanisms remain unclear. Our study aimed to investigate the expression characteristics of γ-catenin in AML patients, explore the mechanisms by which γ-catenin regulates ß-catenin, and discuss the feasibility of targeting γ-catenin for AML treatment. METHODS: The mRNA expression levels of γ-catenin in AML patients were measured by qRT-PCR. Cell proliferation was examined via Cell Counting Kit-8 (CCK-8) assays. The expression levels of related proteins were measured via Western blotting. Specific siRNA was used to modulate the expression level of the γ-catenin gene. Apoptosis and cell cycle distribution were quantified by flow cytometry. The subcellular localization of γ-catenin and ß-catenin was examined via immunofluorescence with a confocal laser scanning microscope. RESULTS: Overexpression of γ-catenin was frequently observed in AML and correlated with poor prognosis. Consistent with this finding, suppression of γ-catenin in the AML cell line THP-1 induced growth inhibition, promoted apoptosis and blocked ß-catenin nuclear translocation. Interestingly, γ-catenin knockdown sensitized THP-1 cells to cytotoxic chemotherapeutic agents such as cytarabine and homoharringtonine and further inhibited ß-catenin nuclear localization. Moreover, our data implied the relationship between γ-catenin and GSK3ß (whose effect on ß-catenin is mediated by its own phosphorylation), which may be the principal mechanism underlying the anti-AML effect of γ-catenin inhibition. CONCLUSION: Taken together, our results revealed a potential role of γ-catenin in AML pathogenesis-mainly through the inhibition of GSK3ß-mediated nuclear localization of ß-catenin-and indicate that targeting γ-catenin might offer new AML treatments.

THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial-Mesenchymal Transformation in Lipid Nephrotoxicity.

Hyperlipidemia, an important risk factor for cardiovascular and end-stage renal diseases, often aggravates renal injury and compromises kidney function. Here, histological analysis of human kidney samples revealed that high lipid levels induced the development of renal fibrosis. To elucidate the mechanism underlying lipid nephrotoxicity, we used two types of mouse models (Apoe-/- and C57BL/6 mice fed a 45 and 60% high-fat diet, respectively). Histological analysis of kidney tissues revealed high-lipid-induced renal fibrosis and inflammation; this was confirmed by examining fibrotic and inflammatory marker expression using Western blotting and real-time polymerase chain reaction. Oxidized low-density lipoprotein (OX-LDL) significantly induced the fibrotic response in HK-2 tubular epithelial cells. RNA-sequencing and Gene Ontology analysis of differentially expressed mRNAs in OX-LDL-treated HK-2 tubular epithelial cells and real-time PCR validation in Apoe-/- mice showed that the expression of thrombospondin-1 (THBS1) in the high-fat group was significantly higher than that of the other top known genes, along with significant overexpression of its receptor CD47. THBS1 knockdown cells verified its relation to OX-LDL-induced fibrosis and inflammation. Liquid chromatography tandem mass spectrometry and STRING functional protein association network analyses predicted that THBS1/CD47 modulated the interaction between γ-catenin and E-cadherin and was involved in epithelial-mesenchymal transition, which was supported by immunoprecipitation and immunohistochemistry. CD47 downregulation following transfection with small-hairpin RNA in OX-LDL-treated tubular epithelial cells and treatment with anti-CD47 antibody restored the expression of E-cadherin and attenuated renal injury, fibrosis, and inflammatory response in OX-LDL-treated cells and in type 2 diabetes mellitus. These findings indicate that CD47 may serve as a potential therapeutic target in long-term lipid-induced kidney injury.

Increased expression of plakoglobin is associated with upregulated MAPK and PI3K/AKT signalling pathways in early resectable pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types, and it is associated with a 5-year survival rate of <10% due to limited early detection methods and ineffective therapeutic options. Thus, an improved understanding of the mechanisms involved in the early stages of PDAC tumorigenesis is crucial in order to identify potential novel diagnostic and therapeutic targets. The most common signalling aberrations in PDAC occur in the Wnt/Notch signalling pathway, as well as within the epidermal growth factor receptor (EGFR) pathway and its associated ligands, EGF and transforming growth factor-ß. In addition, the RAS family of oncogenes, which act downstream of EGFR, are found mutated in most pancreatic cancer samples. Plakoglobin, a component of the EGFR signalling pathway, serves an important role in normal cell adhesion; however, its role in PDAC is largely unknown. The present study used transcriptome sequencing and focussed proteome microarrays to identify dysregulated genes and proteins in PDAC. The presence of upregulated plakoglobin expression levels was identified as a distinguishing feature between the PDAC microenvironment and normal pancreatic tissue. Furthermore, plakoglobin was demonstrated to be associated with the differential upregulation of the PI3K/AKT and MAPK signalling pathways in the tumour microenvironment, which suggested that it may serve an important role in PDAC tumourigenesis.

Cleavage of Desmosomal Cadherins Promotes γ-Catenin Degradation and Benefits Wnt Signaling in Coxsackievirus B3-Induced Destruction of Cardiomyocytes.

Coxsackievirus B3 (CVB3) is the primary etiologic agent of viral myocarditis, a major heart disease that occurs predominantly in children and young adolescents. In the heart, intercalated disks (ICD) are important structural formations that connect adjacent cardiomyocytes to maintain cardiac architecture and mediate signal communication. Deficiency in ICD components, such as desmosome proteins, leads to heart dysfunction. γ-catenin, a component protein of desmosomes, normally binds directly to desmocollin-2 and desmoglein-2. In this study, we found that CVB3 infection downregulated γ-catenin at the protein level but not the mRNA level in mouse HL-1 cardiomyocytes. We further found that this reduction of γ-catenin protein is a result of ubiquitin proteasome-mediated degradation, since the addition of proteasome inhibitor MG132 inhibited γ-catenin downregulation. In addition, we found that desmocollin-2 and desmoglein-2 were cleaved by both viral protease 3C and virus-activated cellular caspase, respectively. These cleavages led to the release of bound γ-catenin from the desmosome into the cytosol, resulting in rapid degradation of γ-catenin. Since γ-catenin shares high sequence homology with ß-catenin in binding the TCF/LEF transcription factor, we further studied the effect of γ-catenin degradation on Wnt/ß-catenin signaling. Luciferase assay showed that γ-catenin expression inhibited Wnt/ß-catenin signaling. This finding was substantiated by qPCR to show that overexpression of γ-catenin downregulated transcription of Wnt signal target genes, c-myc and MMP9, while silencing γ-catenin upregulated these target genes. Finally, we demonstrated that γ-catenin expression inhibited CVB3 replication. In search for the underlying mechanism, we found that silencing γ-catenin caused down-regulation of interferon-ß and its stimulated antiviral genes MDA5, MAVS, and ISG15. Taken together, our results indicate, for the first time, that CVB3 infection causes cardiomyocyte death through, at least in part, direct damage to the desmosome structure and reduction of γ-catenin protein, which in return promotes Wnt/ß-catenin signaling and downregulates interferon-ß stimulated immune responses.

γ-catenin alleviates cardiac fibrosis through inhibiting phosphorylation of GSK-3ß.

Cardiac fibrosis is a common pathological change of many cardiovascular diseases. ß-catenin has been shown to promote fibrosis. However, the precise role of its homolog γ-catenin in the process of fibrosis remains largely unclear. In this study, we found that the expression of γ-catenin was significantly decreased in angiotensin Ⅱ (Ang Ⅱ)-induced cardiac fibrosis model, contrary to most reports of ß-catenin. Overexpression of γ-catenin in cardiac fibroblasts (CFs) significantly inhibited the expression of α-smooth muscle actin (α-SMA), whereas knocking down the expression of γ-catenin with siRNA promoted the occurrence of cardiac fibrosis. Mechanistically, γ-catenin could bind to GSK-3ß to inhibit the phosphorylation of GSK-3ß, therefore preventing cardiac fibrosis. Our study shows that γ-catenin is an important protective factor in cardiac fibrosis, which provides a new potential target for the treatment of cardiac fibrosis.

γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia.

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1+ B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1+ B-ALL.

Beyond cell-cell adhesion: Plakoglobin and the regulation of tumorigenesis and metastasis.

Plakoglobin (also known as γ-catenin) is a member of the Armadillo family of proteins and a paralog of ß-catenin. Plakoglobin is a component of both the adherens junctions and desmosomes, and therefore plays a vital role in the regulation of cell-cell adhesion. Similar to ß-catenin, plakoglobin is capable of participating in cell signaling in addition to its role in cell-cell adhesion. In this context, ß-catenin has a well-documented oncogenic potential as a component of the Wnt signaling pathway. In contrast, while some studies have suggested a tumor promoting activity of plakoglobin in a cell/malignancy specific context, it generally acts as a tumor/metastasis suppressor. How plakoglobin acts as a growth/metastasis inhibitory protein has remained, until recently, unclear. Recent evidence suggests that plakoglobin may suppress tumorigenesis and metastasis by multiple mechanisms, including the suppression of oncogenic signaling, interactions with various proteins involved in tumorigenesis and metastasis, and the regulation of the expression of genes involved in these processes. This review is primarily focused on various mechanisms by which plakoglobin may inhibit tumorigenesis and metastasis.

The clinical significance of γ-catenin in acute myeloid leukemia.

Dysregulation of γ-catenin may function as an oncogenic factor in various malignancies. We investigated γ-catenin expression in acute myeloid leukemia (AML) and explored its role in the pathogenesis of AML. γ-Catenin was significantly overexpressed in AML patients compared to healthy donors. The γ-catenin expression in AML patients with lower white blood cells (<30×10(9)/L) was significantly higher than those with higher white blood cells (≥30×10(9)/L). The expression levels of γ-catenin in AML patients with mutated CEBPα were significantly higher than those with unmutated CEBPα. AML patients with lower γ-catenin levels were more likely to achieve complete remission compared with patients who have higher γ-catenin levels. In K562 cells, γ-catenin knockdown suppressed cellular proliferation, while the cellular migration was greatly enhanced. Moreover, knocking down of γ-catenin enhanced the cytotoxicity of decitabine in K562 cells. Our investigation has indicated a potential role of γ-catenin in the pathogenesis of AML.

Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib.

Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can eliminate quiescent LSCs in CML, little is known about the underlying mechanism that HDACis kill LSCs. By fishing with a biotin-labeled probe, we identified that HDACi JSL-1 bound to the protein γ-catenin. γ-Catenin expression was higher in LSCs from CML patients than normal hematopoietic stem cells. Silencing γ-catenin in human CML CD34(+) bone-marrow (BM) cells sufficiently eliminated LSCs, which suggests that γ-catenin is required for survival of CML LSCs. Pharmacological inhibition of γ-catenin thwarted survival and self-renewal of human CML CD34(+) cells in vitro, and of murine LSCs in BCR-ABL-driven CML mice. γ-Catenin inhibition reduced long-term engraftment of human CML CD34(+) cells in NOD.Cg-Prkdc (scid) II2rg (tm1Sug)/JicCrl (NOG) mice. Silencing γ-catenin by shRNA in human primary CD34(+) cells did not alter ß-catenin, implying a ß-catenin-independent role of γ-catenin in survival and self-renewal of CML LSCs. Taken together, our findings validate that γ-catenin may be a novel therapeutic target of LSCs, and suppression of γ-catenin by HDACi may explain elimination of CML LSCs.