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Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells.

ABSTRACT: We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1), MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression.

SUBMITTER: Sassano A

PROVIDER: S-EPMC4524119 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells.

Sassano Antonella A Mavrommatis Evangelos E Arslan Ahmet Dirim AD Kroczynska Barbara B Beauchamp Elspeth M EM Khuon Satya S Chew Ten-Leong TL Green Kathleen J KJ Munshi Hidayatullah G HG Verma Amit K AK Platanias Leonidas C LC

Molecular and cellular biology 20150526 15

We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1), MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 ...[more]

PMID: 26012550

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Project description:Among all types of kidney diseases, renal cell carcinoma (RCC) has the highest mortality, recurrence and metastasis rates, which results in high numbers of tumor‑associated mortalities in China. Identifying a novel therapeutic target has attracted increasing attention. Bromodomain and extraterminal domain (BET) proteins have the ability to read the epigenome, leading to regulation of gene transcription. As an important member of the BET family, bromodomain testis‑specific protein (BRDT) has been well studied; however, the mechanism underlying BRDT in the regulation of RCC has not been fully investigated. Eukaryotic translation initiation factor 4E‑binding protein 1 (eIF4EBP1) is a binding partner of eIF4E that is involved in affecting the progression of various cancer types via regulating gene transcription. To identify novel regulators of eIF4EBP1, an immunoprecipitation assay and mass spectrometry analysis was performed in RCC cells. It was revealed that eIF4EBP1 interacted with BRDT, a novel interacting protein. In addition, the present study further demonstrated that BRDT inhibitors PLX51107 and INCB054329 blocked the progression of RCC cells, along with suppressing eIF4EBP1 and c‑myc expression. Small interfering (si) RNAs were used to knock down BRDT expression, which suppressed RCC cell proliferation and eIF4EBP1 protein expression. In addition, overexpression of eIF4EBP1 partially abolished the inhibited growth function of PLX51107 but knocking down eIF4EBP1 improved the inhibitory effects of PLX51107. Furthermore, treatment with PLX51107 or knockdown of BRDT expression decreased c‑myc expression at both the mRNA and protein levels, and attenuated its promoter activity, as determined by luciferase reporter assays. PLX51107 also significantly altered the interaction between the c‑myc promoter with eIF4EBP1 and significantly attenuated the increase of RCC tumors, accompanied by decreased c‑myc mRNA and protein levels in vivo. Taken together, these data suggested that blocking of BRDT by PLX51107, INCB054329 or BRDT knockdown suppressed the growth of RCC via decreasing eIF4EBP1, thereby leading to decreased c‑myc transcription levels. Considering the regulatory function of BET proteins in gene transcription, the present study suggested that there is a novel mechanism underlying eIF4EBP1 regulation by BRDT, and subsequently decreased c‑myc in RCC, and further identified a new approach by regulating eIF4EBP1 or c‑myc for enhancing BRDT‑targeting RCC therapy.

Dataset Information

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells.

Publications

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells.

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