RESUMEN
WBP2 transcription coactivator is an emerging oncoprotein and a key node of convergence between EGF and Wnt signaling pathways. Understanding how WBP2 is regulated has important implications for cancer therapy. WBP2 is tightly controlled by post-translational modifications, including phosphorylation and ubiquitination, leading to changes in subcellular localization, protein-protein interactions, and protein turnover. As the function of WBP2 is intricately linked to YAP and TAZ, we hypothesize that WBP2 is negatively regulated by the Hippo tumor suppressor pathway. Indeed, MST is demonstrated to negatively regulate WBP2 expression in a kinase-dependent but LATS-independent manner. This was observed in the majority of the breast cancer cell lines tested. The effect of MST was enhanced by SAV and concomitant with the inhibition of the transcription co-activation, in vitro and in vivo tumorigenesis activities of WBP2, resulting in good prognosis in xenografts. Downregulation of WBP2 by MST involved miRNA but not proteasomal or lysosomal degradation. Our data support the existence of a novel MST-Dicer signaling axis, which in turn regulates both WBP2 CDS- and UTR-targeting miRNAs expression, including miR-23a. MiR-23a targets the 3'UTR of WBP2 mRNA directly. Significant inverse relationships between WBP2 and MST or miR23a expression levels in clinical specimens were observed. In conclusion, WBP2 is a target of the Hippo/MST kinase; MST is identified as yet another rheostat in the regulation of WBP2 and its oncogenic function. The findings have implications in targeted therapeutics and precision medicine for breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , ARN Helicasas DEAD-box/metabolismo , Ribonucleasa III/metabolismo , Transactivadores/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular Tumoral , ARN Helicasas DEAD-box/genética , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Vía de Señalización Hippo , Humanos , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/fisiología , Células MCF-7 , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Oncogénicas/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Ribonucleasa III/genética , Transducción de Señal/genética , Transactivadores/fisiología , Factores de Transcripción/metabolismo , Vía de Señalización WntRESUMEN
BACKGROUND: Transcription factors are commonly deregulated in various cancers. Here, we evaluated role of ELF3 in pathogenesis of bladder carcinoma (BCa). MATERIALS AND METHODS: We confirmed ELF3 expression pattern in BCa cell lines using western blot; and in different grades of tumors using Immunohistochemistry. Cell invasion assay was employed to demonstrate potential role of ELF3 in EMT. RESULTS AND CONCLUSION: ELF3 showed selective expression in low-grade cell lines and tumor tissues. Overexpression of ELF3 in mesenchymal cell line UMUC3 resulted in reduced invasion and decreased expression of mesenchymal markers. We observed association of low ELF3 expression with increased risk and overall poor survival using publicly available data. ELF3-modulated reversal of EMT might be a useful strategy in the treatment of bladder cancer.
Asunto(s)
Proteínas de Unión al ADN/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción/genética , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias de la Vejiga Urinaria/patología , Biomarcadores de Tumor , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Biología Computacional/métodos , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Familia de Multigenes , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas c-ets/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain largely unclear. Here we describe how miR-615-3p represses hTERT expression. mir-615-3p is located in an intron of the HOXC5 gene, a member of the highly conserved homeobox family of transcription factors controlling embryogenesis and development. Unexpectedly, we found that HoxC5 also represses hTERT expression by disrupting the long-range interaction between hTERT promoter and its distal enhancer. The 3'UTR of hTERT and its upstream enhancer region are well conserved in long-lived primates. Both mir-615-3p and HOXC5 are activated upon differentiation, which constitute a feed-forward loop that coordinates transcriptional and post-transcriptional repression of hTERT during cellular differentiation. Deregulation of HOXC5 and mir-615-3p expression may contribute to the activation of hTERT in human cancers.