RESUMO
The poly(A) tail at the 3' end of mRNAs determines their stability, translational efficiency, and fate. The shortening of the poly(A) tail, and its efficient removal, triggers the degradation of mRNAs, thus, regulating gene expression. The process is catalyzed by a family of enzymes, known as deadenylases. As the dysregulation of gene expression is a hallmark of cancer, understanding the role of deadenylases has gained additional interest. Herein, the genetic association network shows that CNOT6 and CNOT7 are the most prevalent and most interconnected nodes in the equilibrated diagram. Subsequent silencing and transcriptomic analysis identifies transcripts possibly regulated by specific deadenylases. Furthermore, several gene ontologies are enriched by common deregulated genes. Given the potential concerted action and overlapping functions of deadenylases, we examined the effect of silencing a deadenylase on the remaining ones. Our results suggest that specific deadenylases target unique subsets of mRNAs, whilst at the same time, multiple deadenylases may affect the same mRNAs with overlapping functions.
Assuntos
Carcinoma , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Actin-Related Protein-Testis1 (ARP-T1)/ACTRT1 gene mutations cause the Bazex-Dupré-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis, and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) that includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. In agreement, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in interphase. Tissue samples from ARP-T1-associated BDCS patients have reduced ciliary length. The severity of the shortened cilia significantly correlates with the ARP-T1 levels, which was further validated by ACTRT1 knockdown in culture cells. Thus, we propose that ARP-T1 participates in the regulation of cilia length and that ARP-T1-associated BDCS is a case of skin cancer with ciliopathy characteristics.
Assuntos
Carcinoma Basocelular/patologia , Cílios/patologia , Ciliopatias/patologia , Hipotricose/patologia , Queratinócitos/patologia , Proteínas dos Microfilamentos/metabolismo , Neoplasia de Células Basais/patologia , Neoplasias Cutâneas/patologia , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Cílios/metabolismo , Ciliopatias/genética , Ciliopatias/metabolismo , Humanos , Hipotricose/genética , Hipotricose/metabolismo , Queratinócitos/metabolismo , Proteínas dos Microfilamentos/genética , Mutação , Neoplasia de Células Basais/genética , Neoplasia de Células Basais/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide, mainly due to late diagnosis, poor prognosis and tumor heterogeneity. Thus, the need for biomarkers that will aid classification, treatment and monitoring remains intense and challenging and depends on the better understanding of the tumor pathobiology and underlying mechanisms. The deregulation of gene expression is a hallmark of cancer and a critical parameter is the stability of mRNAs that may lead to increased oncogene and/or decreased tumor suppressor transcript and protein levels. The shortening of mRNA poly(A) tails determines mRNA stability, as it is usually the first step in mRNA degradation, and is catalyzed by deadenylases. Herein, we assess the clinical significance of deadenylases and we study their role on gene expression in squamous cell lung carcinoma (SCC). METHODS: Computational transcriptomic analysis from a publicly available microarray was performed in order to examine the expression of deadenylases in SCC patient samples. Subsequently we employed real-time PCR in clinical samples in order to validate the bioinformatics results regarding the gene expression of deadenylases. Selected deadenylases were silenced in NCI-H520 and Hep2 human cancer cell lines and the effect on gene expression was analyzed with cDNA microarrays. RESULTS: The in silico analysis revealed that the expression of several deadenylases is altered in SCC. Quantitative real-time PCR showed that four deadenylases, PARN, CNOT6, CNOT7 and NOC, are differentially expressed in our SCC clinical samples. PARN overexpression correlated with younger patient age and CNOT6 overexpression with non-metastatic tumors. Kaplan-Meier analysis suggests that increased levels of PARN and NOC correlate with significantly increased survival. Gene expression analysis upon PARN and NOC silencing in lung cancer cells revealed gene expression deregulation that was functionally enriched for gene ontologies related to cell adhesion, cell junction, muscle contraction and metabolism. CONCLUSIONS: Our results highlight the clinical significance of PARN and NOC on the survival in SCC diagnosed patients. We demonstrate that the enzymes are implicated in important phenotypes pertinent to cancer biology and provide information on their role in the regulation of gene expression in SCC. Overall, our results support an emerging role for deadenylases in SCC and contribute to the understanding of their role in cancer biology.