Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma

• Pyk2 plays a tumor-promoting role in MM progression via modulation of the Wnt/ b-catenin signaling pathway.• Pyk2 inhibitors represent a new therapeutic option against MM.Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared with healthy individuals. By using loss-of-function approaches, we found that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cellcycle progression, and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/b-catenin signaling by destabilizing b-catenin, leading to downregulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718 effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM. (Blood. 2014;124(17):2675-2686

show abstract

“…20,21 All the intensity files were MAS5 transformed and the data normalized to the median, as previously reported. 22 …”

Section: Gene Expression Analysismentioning

confidence: 99%

Pyk2 promotes tumor progression in multiple myeloma

Zhang

Moschetta

Huynh

et al. 2014

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…TNFRSF18 (tumor necrosis factor receptor superfamily, member 18, also known as AITR or GITR ), a member of the tumor necrosis factor receptor (TNF‐R) superfamily, plays a crucial role in modulating immune response and inflammation . It was inactivated during tumor progression in multiple myeloma (MM) through promoter CpG island methylation and was identified as a novel tumor suppressor gene . Moreover, GITR was found to be significantly downregulated in MM patients and cell lines, and its expression can enhance the sensitivity to bortezomib by inhibiting bortezomib‐induced NF‐κB activation .…”

Section: Discussionmentioning

confidence: 99%

Identification of a six‐gene signature with prognostic value for patients with endometrial carcinoma

et al. 2018

View full text Add to dashboard Cite

Uterine corpus endometrial carcinoma (UCEC) is frequently diagnosed among women worldwide. However, there are different prognostic outcomes because of heterogeneity. Thus, the aim of the current study was to identify a gene signature that can predict the prognosis of patients with UCEC. UCEC gene expression profiles were first downloaded from the The Cancer Genome Atlas (TCGA) database. After data processing and forward screening, 11 390 key genes were selected. The UCEC samples were randomly divided into training and testing sets. In total, 996 genes with prognostic value were then examined by univariate Cox survival analysis with a P‐value <0.01 in the training set. Next, using robust likelihood‐based survival modeling, we developed a six‐gene signature (CTSW, PCSK4, LRRC8D, TNFRSF18, IHH, and CDKN2A) with a prognostic function in UCEC. A prognostic risk score system was developed by multivariate Cox proportional hazard regression based on this six‐gene signature. According to the Kaplan‐Meier curve, patients in the high‐risk group had significantly poorer overall survival (OS) outcomes than those in the low‐risk group (log‐rank test P‐value <0.0001). This signature was further validated in the testing dataset and the entire TCGA dataset. In conclusion, we conducted an integrated study to develop a six‐gene signature for the prognostic prediction of patients with UCEC. Our findings may provide novel biomarkers for prognosis and have significant implications in the understanding of therapeutic targets for UCEC.

show abstract

“…Hypermethylation of RASD1, for example, has been correlated with resistance of MM to dexamethasone (Nojima et al 2009). Inappropriate DNA methylation of TNFRSF18 (also known as GITR) (Liu et al 2013), MIR34B/C (Wong et al 2011), or the combined inactivation of genes GPX3, RBP1, SPARC, and TGFBI (Kaiser et al 2013) have been associated with poor prognosis, survival, and disease progression in patients with MM.…”

mentioning

confidence: 99%

Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

et al. 2015

View full text Add to dashboard Cite

While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cellspecific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.

show abstract

Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma

Cited by 14 publications

References 37 publications

Pyk2 promotes tumor progression in multiple myeloma

Pyk2 promotes tumor progression in multiple myeloma

Identification of a six‐gene signature with prognostic value for patients with endometrial carcinoma

Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

Contact Info

Product

Resources

About