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A complex with poly(A) binding protein cytoplasmic 1 and EWS facilitates oncogenic ETS transcription factor function in prostate cells

ABSTRACT: The ETS transcription factor ERG is aberrantly expressed in approximately 50% of prostate tumors due to chromosomal rearrangements such as TMPRSS2/ERG. The ability of ERG to drive oncogenesis in prostate epithelial cells requires interaction with distinct co-activators, such as the RNA-binding protein EWS. Here, we find that ERG has both direct and indirect interactions with EWS, and the indirect interaction is mediated by the poly-A RNA-binding protein PABPC1. PABPC1 directly bound both ERG and EWS. ERG expression in prostate cells promoted PABPC1 localization to the nucleus and recruited PABPC1 to ERG/EWS binding sites in the genome. Knockdown of PABPC1 in prostate cells abrogated ERG-mediated phenotypes and decreased the ability of ERG to activate transcription. These findings define a complex including ERG and the RNA-binding proteins EWS and PABPC1 that represents a novel therapeutic target for ERG-positive prostate cancer and identify a novel nuclear role for PABPC1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226472 | GEO | 2023/11/06

REPOSITORIES: GEO

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Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen Test Cohort: 388 cases from the population based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); Validation cohort: The PhysiciansM-bM-^@M-^Y Health Study (PHS) cohort included 116 US men diagnosed with incidental prostate cancer between 1983 and 2003; 455 cases were annotated for TMPRSS2-ERG fusion. Test Set: GSM208029 ... GSM208392 Validation Set: GSM208404 ... GSM208512

Project description:Antineoplastic effects of siRNA against TMPRSS2-ERG junction oncogene in prostate cancer: from molecular and cellular studies to preclinical investigations. Background of the study.:TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer, and its expression is frequently associated with poor prognosis. We knockdown by siRNA the two TMPRSS2-ERG fusion variants (III and IV) most frequently identified in patients’ biopsies and found an inhibition of TMPRSS2-ERG of above 70% in human prostate cancer VCaP cell line expressing TMPRSS2-ERG junction oncogene. To point out genes regulated after TMPRSS2-ERG oncogene silencing, microarray analysis was performed.. Materiel and Methods. Human prostate cancer VCaP cell line expressing TMPRSS2-ERG oncogene (ATCC® CRL-2876™ Manassas, USA) was grown in Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Cergy-Pontoise, France) supplemented with 10% fetal bovine serum (FBS), 100 units/ml penicillin and 100 μg/ml streptomycin (Invitrogen). Cells were incubated at 37°C in a humidified atmosphere containing 5% CO2. Transfection was carried out using Lipofectamine RNAiMAX transfecting agent (Invitrogen) according to manufacturer's instructions. Briefly, 8×105 VCaP cells were seeded in six-well plates in DMEM supplemented with 10% FCS, penicillin (100U/ml) and streptomycin (10µg/ml) and transfected with 50 nM siRNA TMPRSS2-ERG III, siRNA TMPRSS2-ERG IV and siRNA Control and 6 μL Lipofectamine® RNAiMAX. Cells were incubated with siRNA for 48h. At the end of the treatments, total RNAs of untreated cells (NT) and transfected cells were extracted using RNeasy mini-kit (Quiagen, Courtaboeuf, France). Three independent experiments were performed. Results. Microarray analysis confirmed ERG inhibition by both siRNA TMPRSS2-ERG III and IV and revealed a common down-regulated gene, ADRA2A, involved in cell proliferation and migration. Experiments are performed with Agilent Whole Genome 8x60K (028004) microarray. In triplicate with a non treated control cells, a control with ascramble siRNA, a siRNA TMPRSS2-ERG III, a siRNA TMPRSS2 IV.

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A complex with poly(A) binding protein cytoplasmic 1 and EWS facilitates oncogenic ETS transcription factor function in prostate cells

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