Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer

Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt-11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer

Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe

Peer reviewe

Swedish population substructure revealed by genome-wide single nucleotide polymorphism data

Peer reviewe

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

The small ubiquitin-like modifier (SUMO) pathway regulates the hallmark properties of cancer cells. Moreover, alterations in activity and in levels of SUMO machinery components have been observed in human cancer. Due to the reversible nature of this post-translational protein modification, the balance between SUMOylation and the removal of SUMO is critical. Early-phase clinical trials are currently evaluating the safety and efficacy of SUMO pathway inhibition in cancer patients. In this comprehensive review, we critically discuss the potential of targeting the SUMO pathway as a therapeutic option for cancer. </p

Frizzled-8 integrates Wnt-11 and transforming growth factor-beta signaling in prostate cancer

Wnt-11 promotes cancer cell migration and invasion independently of beta-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD(8) is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-beta signals to promote EMT. FZD(8) mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD(8) in cancer, correlating with Wnt-11. FZD(8) co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD(8) silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-beta/Smad-dependent signaling. Mechanistically, FZD(8) forms a TGF-beta-regulated complex with TGF-beta receptors that is mediated by the extracellular domains of FZD(8) and TGFBR1. Targeting FZD(8) may therefore inhibit aberrant activation of both Wnt and TGF-beta signals in prostate cancer

Identification of New Alleles and the Determination of Alleles and Genotypes Frequencies at the CYP2D6 Gene in Emiratis

CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20–25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls

Proteomic profiling identifies a direct interaction between heat shock transcription factor 2 and the focal adhesion adapter talin‐1

Heat shock factor 2 (HSF2) is a versatile transcription factor that regulates gene expression under stress conditions, during development, and in disease. Despite recent advances in characterizing HSF2‐dependent target genes, little is known about the protein networks associated with this transcription factor. In this study, we performed co‐immunoprecipitation coupled with mass spectrometry analysis to identify the HSF2 interactome in mouse testes, where HSF2 is required for normal sperm development. Endogenous HSF2 was discovered to form a complex with several adhesion‐associated proteins, a finding substantiated by mass spectrometry analysis conducted in human prostate carcinoma PC‐3 cells. Notably, this group of proteins included the focal adhesion adapter protein talin‐1 (TLN1). Through co‐immunoprecipitation and proximity ligation assays, we demonstrate the conservation of the HSF2‐TLN1 interaction from mouse to human. Additionally, employing sequence alignment analyses, we uncovered a TLN1‐binding motif in the HSF2 C terminus that binds directly to multiple regions of TLN1 in vitro. We provide evidence that the 25 C‐terminal amino acids of HSF2, fused to EGFP, are sufficient to establish a protein complex with TLN1 and modify cell–cell adhesion in human cells. Importantly, this TLN1‐binding motif is absent in the C‐terminus of a closely related HSF family member, HSF1, which does not form a complex with TLN1. These results highlight the unique molecular characteristics of HSF2 in comparison to HSF1. Taken together, our data unveil the protein partners associated with HSF2 in a physiologically relevant context and identifies TLN1 as the first adhesion‐related HSF2‐interacting partner

Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90: MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a "reactivating'' mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2