Browsing by Author "Almami, Amal"

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    ING3 Expression in Prostate Cancer and Its Association with ERG Gene Rearrangements and Patient Outcome
    (2014-02-05) Almami, Amal; Bismar, Tarek; Demetrick, Douglas
    ETS Related Gene (ERG) rearrangement is one of the most common genetic changes seen in roughly about 50% of prostate cancer (PCA) cases. The inhibitor of growth family member 3 (ING3) is a member of the ING tumor suppressor family. The deregulation of ING3 expression has been reported in various types of cancers. However, to date the role and function of ING3 in PCA as well as its relationship to ERG gene rearrangement has not been studied. Our initial observation from microarray expression profiling showed that ING3 was down-regulated in ERG positive prostate cancer samples in comparison to ERG negative tumors. In this work, we examined the expression and localization of ING3 in prostate cancer cell lines and tissue samples and its association to clinical outcome. We documented a significant association between ERG and ING3 and showed a significant association to the patients’ clinical outcome, thus highlighting a potential role for ING3 in prostate cancer progression.
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    ING3 promotes prostate cancer growth by activating the androgen receptor
    (2017-05-16) Nabbi, Arash; McClurg, Urszula L; Thalappilly, Subhash; Almami, Amal; Mobahat, Mahsa; Bismar, Tarek A; Binda, Olivier; Riabowol, Karl T
    Abstract Background The androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development. Methods Biopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3. Results We find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n = 498) and a prostate cancer tissue microarray (n = 256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more accurate prognosis in primary prostate cancer. Conclusions In contrast to the majority of previous reports suggesting tumor suppressive functions in other cancers, our observations identify a clear oncogenic role for ING3, which acts as a co-activator of AR in prostate cancer. Data from TCGA and our previous and current tissue microarrays suggest that ING3 levels correlate with AR levels and that in patients with low levels of the receptor, ING3 level could serve as a useful prognostic biomarker.