ING3 is associated with increased cell invasion and lethal outcome in ERG-negative prostate cancer patients

Almami, Amal; Hegazy, Samar; Nabbi, Arash; Alshalalfa, Mohammed; Salman, Asma; Abou-Ouf, Hatem; Riabowol, Karl; Bismar, Tarek A.

doi:10.1007/s13277-016-4802-y

Cited by 13 publications

(13 citation statements)

References 30 publications

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“…Consistent with a previous report [25], ING3 also decreased the migration of AR-negative PC3 and DU145 cells (Additional file 1: Figure S5A, B), suggesting that an AR-independent mechanism exists by which ING3 can affect these cells. ING3 knockdown in LNCaP cells also reduced MB-induced filopodia formation as visualized by Alexa 568-conjugated phalloidin staining (Additional file 1: Figure S5D, E), consistent with ING3 having an effect on migration, in addition to effects on cell growth.…”

Section: Resultssupporting

confidence: 92%

“…Since ING3 levels regulate PC cell proliferation and correlate with prognosis in patients with ERG-negative PC, we asked whether ING3 had any function in PC cells and whether it interacts with the AR [25, 26, 28]. Correlation analysis using The Cancer Genome Atlas (TCGA) prostate adenocarcinoma cohort data ( n = 498) indicated that ING3 and AR mRNA levels were positively correlated (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This is in line with our findings that ING3 modulated cell migration and that higher ING3 levels correlated with poorer outcome in the subset of patients having tumors with low levels of AR. We recently found that high levels of ING3 also correlate with poorer survival in ERG-negative PC [25]. Although the interplay between ERG and AR remains unclear, several studies have suggested that the ERG fusion protein inhibits AR expression and activity at several loci [57], supporting the idea that ING3 can potentiate the activity of the AR pathway, particularly when AR inhibitory factors such as ERG are absent.…”

Section: Discussionmentioning

confidence: 98%

“…In a recent screening study, it was noted that high ING3 levels correlate with worse prognosis in patients with erythroblast transformation-specific-related gene (ERG) negative PC, and that a ten-gene signature that correlates with patient survival in these cancers included ING3 [25, 26]. However, the mechanism by which ING3 contributes to ERG-negative PC and its role in PC biology in general were not characterized.…”

Section: Introductionmentioning

confidence: 99%

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ING3 promotes prostate cancer growth by activating the androgen receptor

Nabbi

McClurg

Thalappilly

et al. 2017

BMC Med

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BackgroundThe 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.MethodsBiopsies 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.ResultsWe 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.ConclusionsIn 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0854-0) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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ING3 promotes prostate cancer growth by activating the androgen receptor

Nabbi

McClurg

Thalappilly

et al. 2017

BMC Med

Self Cite

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“…However, the involvement of ING3 in carcinogenesis has not been completely elucidated yet. Indeed, several studies suggest that ING3 would act as an oncogene in prostate cancer by increasing expression of androgen-regulated genes and is associated with poor prognosis in ERG-negative prostate cancer (108)(109)(110).…”

Section: Ing3 Role and Ncrnas Involvementmentioning

confidence: 99%

Regulat-INGs in tumors and diseases: Focus on ncRNAs

et al. 2019

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ING family genes (Inhibitor of Growth) are tumor suppressor genes that play a vital role in cell homeostasis. It has been shown that their expression is lost or diminished in many cancers and other diseases. The main mechanisms by which they are regulated in oncogenesis have not yet been fully elucidated. The involvement of non-coding RNAs (ncRNAs) and in particular microRNAs (miRNAs) in post-transcriptional gene regulation is well established. miRNAs are short sequences (18 to 25 nucleotides) that can bind to the 3 'UTR sequence of the targeted messenger RNA (mRNA), leading to its degradation or translational repression. Interactions between the ING family and miRNAs have been described in some cancers but also in other diseases. The involvement of miRNAs in ING family regulation opens up new fields of investigation, particularly for targeted therapies. In this review, we will summarize the regulatory mechanisms at the RNA and protein level of the ING family and focus on the interactions with ncRNAs.

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ING5 inhibits cancer aggressiveness by inhibiting Akt and activating p53 in prostate cancer

Barlak

Capik

Şanli

et al. 2019

Cell Biology International

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Prostate cancer (PCa) is one of the most common types of cancer in men. In several recent studies, chromosomal deletions in the q arm of chromosome 2, where ING5 resides within, have been identified in various cancer types including PCa. In this study, we investigate the role of ING5 as a tumor suppressor in PCa. We examined the expression level of ING5 in tissue samples and cell lines using quantitative real‐time polymerase chain reaction and western blot analysis. We tested the in vitro tumor suppressor potential of ING5 in PC3 and LNCaP cells stably overexpressing it using cell viability, colony formation, migration, invasion, and apoptosis assays. We then investigated the effects of ING5 on the Akt and p53 signaling using western blot analysis. We show that ING5 is significantly downregulated in PCa tumor tissue samples and cell lines compared with the corresponding controls. In vitro assays demonstrate that ING5 effectively suppresses proliferative, clonogenic, migratory, and invasive potential and induce apoptosis in PCa cells. ING5 may potentially exert its anti‐tumor potential by inhibiting AKT and inducing p53 signaling pathways. Our findings demonstrate that ING5 possesses tumor suppressor roles in vitro, pointing its importance during the prostatic carcinogenesis processes.

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ING3 is associated with increased cell invasion and lethal outcome in ERG-negative prostate cancer patients

Cited by 13 publications

References 30 publications

ING3 promotes prostate cancer growth by activating the androgen receptor

ING3 promotes prostate cancer growth by activating the androgen receptor

Regulat-INGs in tumors and diseases: Focus on ncRNAs

ING5 inhibits cancer aggressiveness by inhibiting Akt and activating p53 in prostate cancer

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