Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression

Lopez, Sandra M.; Agoulnik, Alexander I.; Zhang, Manqi; Peterson, Leif E.; Suarez, Egla; Gandarillas, Gregory A.; Frolov, Anna; Li, Rile; Rajapakshe, Kimal; Coarfa, Christian; Ittmann, Michael; Weigel, Nancy L.; Agoulnik, Irina U.

doi:10.1158/1078-0432.ccr-15-1983

Cited by 23 publications

(20 citation statements)

References 49 publications

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“…It is notable that C1orf64 is required for the enzalutamide-mediated down-regulation of PIP expression. This finding is consistent with the recent observations that AR corepressor N-CoR1 levels decline with the progression of prostate cancer and this process is involved in the development of resistance to bicalutamide treatment [ 38 ]. Therefore, in a similar way, C1orf64 may have a function in mediating the activities of AR inhibitors in breast cancer.…”

Section: Discussionsupporting

confidence: 93%

C1orf64 is a novel androgen receptor target gene and coregulator that interacts with 14-3-3 protein in breast cancer

Naderi

2017

Oncotarget

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This study investigated the network of genes that are co-expressed with androgen receptor (AR) to discover novel AR targets in breast cancer. Bioinformatics analysis of two datasets from breast cancer cell lines resulted in the identification of an AR-gene signature constituted of 98 genes that highly correlated with AR expression. Notably, C1orf64 showed the highest positive correlation with AR across the datasets with a correlation coefficient (CC) of 0.737. In addition, C1orf64 closely correlated with AR expression in primary and metastatic breast tumors and C1orf64 expression was relatively higher in breast tumors with a lower grade and lobular histology. Furthermore, there is a functional interplay between AR and C1orf64 in breast cancer. In this process, AR activation directly represses C1orf64 transcription and C1orf64, in turn, interacts with AR as a corepressor and negatively regulates the AR-mediated induction of prolactin-induced protein (PIP) and AR reporter activity. Moreover, the corepressor effect of C1orf64 results in a reduction of AR binding to PIP promoter. The other aspect of this interplay involves a cross-talk between AR and estrogen receptor (ER) signaling in which C1orf64 silencing intensifies the AR-mediated down-regulation of ER target gene, progesterone receptor. Therefore, the repression of C1orf64 by AR provides an underlying mechanism for the AR inhibitory effects on ER signaling. To elucidate the biochemical mechanisms of C1orf64 function, this study demonstrates that C1orf64 is a phosphothreonine protein that interacts with the chaperone protein 14-3-3. In summary, C1orf64 is a novel AR coregulator and a 14-3-3 binding partner in breast cancer.

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Section: Discussionsupporting

confidence: 93%

C1orf64 is a novel androgen receptor target gene and coregulator that interacts with 14-3-3 protein in breast cancer

Naderi

2017

Oncotarget

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“…2C, D ). Microarray data sets describing LNCaP cells stimulated by 24 h of 10 nM DHT (GSE60721, GSE4636, GSE69330 23 – 25 ) confirmed a slight increase of both DLGAP5 and CCNB1 (Supp Fig. 2E ).…”

Section: Resultsmentioning

confidence: 81%

A functional genomics screen reveals a strong synergistic effect between docetaxel and the mitotic gene DLGAP5 that is mediated by the androgen receptor

et al. 2018

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Based on a molecular classification of prostate cancer using gene expression pathway signatures, we derived a set of 48 genes in critical pathways that significantly predicts clinical outcome in all tested patient cohorts. We tested these genes in a functional genomics screen in a panel of three prostate cancer cell lines (LNCaP, PC3, DU145), using RNA interference. The screen revealed several genes whose knockdown caused strong growth inhibition in all cell lines. Additionally, we tested the gene set in the presence of docetaxel to see whether any gene exhibited additive or synergistic effects with the drug. We observed a strong synergistic effect between DLGAP5 knockdown and docetaxel in the androgen-sensitive line LNCaP, but not in the two other androgen-independent lines. We then tested whether this effect was connected to androgen pathways and found that knockdown of the androgen receptor by si-RNA attenuated the synergy significantly. Similarly, androgen desensitized LNCaP-AI cells had a higher IC50 to docetaxel and did not exhibit the synergistic interaction. Short-term exposure to enzalutamide did not significantly alter the behaviour of parental LNCaP cells. An immunofluorescence analysis in LNCaP cells suggests that under the double insult of DLGAP5 knockdown and docetaxel, cells predominantly arrest in metaphase. In contrast, the knockdown of the androgen receptor by siRNA appears to assist cells to progress through metaphase in to anaphase, even in the presence of docetaxel. Our data suggest that DLGAP5 has a unique function in stabilizing spindle formation and surviving microtubule assault from docetaxel, in an androgen-regulated cell cycle system.

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“…We chose this time point to evaluate changes in transcript levels using Affymetrix microarrays (Supplemental Figure 1A). To determine whether INPP4B regulates AR target genes, we compared AR target genes in LNCaP cells (34) to genes regulated by INPP4B. Expression of a subset of AR target genes was significantly affected by the knockdown of INPP4B (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity

et al. 2018

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Activation and transcriptional reprogramming of AR in advanced prostate cancer frequently coincides with the loss of two tumor suppressors, INPP4B and PTEN, which are highly expressed in human and mouse prostate epithelium. While regulation of AR signaling by PTEN has been described by multiple groups, it is not known whether the loss of INPP4B affects AR activity. Using prostate cancer cell lines, we showed that INPP4B regulates AR transcriptional activity and the oncogenic signaling pathways Akt and PKC. Analysis of gene expression in prostate cancer patient cohorts showed a positive correlation between INPP4B expression and both AR mRNA levels and AR transcriptional output. Using an Inpp4b mouse model, we demonstrated that INPP4B suppresses Akt and PKC signaling pathways and modulates AR transcriptional activity in normal mouse prostate. Remarkably, PTEN protein levels and phosphorylation of S380 were the same in Inpp4b and WT males, suggesting that the observed changes were due exclusively to the loss of INPP4B. Our data show that INPP4B modulates AR activity in normal prostate and its loss contributes to the AR-dependent transcriptional profile in prostate cancer.

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Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression

Cited by 23 publications

References 49 publications

C1orf64 is a novel androgen receptor target gene and coregulator that interacts with 14-3-3 protein in breast cancer

C1orf64 is a novel androgen receptor target gene and coregulator that interacts with 14-3-3 protein in breast cancer

A functional genomics screen reveals a strong synergistic effect between docetaxel and the mitotic gene DLGAP5 that is mediated by the androgen receptor

Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity

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