Cancer/Testis antigens as potential predictors of biochemical recurrence of prostate cancer following radical prostatectomy

Shiraishi, Takeshi; Terada, Naoki; Zeng, Yu; Suyama, Takahito; Luo, Jun; Trock, Bruce J.; Kulkarni, Prakash; Getzenberg, Robert H.

doi:10.1186/1479-5876-9-153

Cited by 70 publications

(77 citation statements)

References 30 publications

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“…A corollary to the bipolar ADT treatment (67) that stems from our model is that higher levels of PAGE4 would predict a better prognosis. Indeed, PAGE4 expression is significantly correlated with longer biochemical recurrence-free time (71). Moreover, it has been noted that in hormone-naive PCa, the median survival of patients with tumors expressing high PAGE4 levels was 8.2 y compared with 3.1 y for patients with tumors expressing negative/low levels of PAGE4 (36), adding further support to our model.…”

Section: Discussionsupporting

confidence: 80%

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Kulkarni

Jolly

Jia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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149

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Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. ProstateAssociated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. HomeodomainInteracting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgendependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgendependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.intrinsic disorder | androgen resistance | prostate cancer | PAGE-4 | phenotypic heterogeneity C ontrary to conventional wisdom that structure defines protein function (1), it is now increasingly evident that a large fraction of the human proteome is composed of intrinsically disordered proteins (IDPs) lacking rigid 3D structure (2-4). IDPs exist as conformational ensembles that are highly malleable, facilitating their interactions with multiple partners. These interactions are "wired" to form scale-free networks (5, 6) that represent the main conduit of information flow in the cell. Furthermore, the organization and properties of such protein interaction networks are evolutionarily conserved, underscoring their functional significance (7).By occupying hub positions in such networks, IDPs play critical roles in many biological processes, such as transcription, translation, and signaling (8, 9). IDPs also participate in higher order phenomena, such as regulation of the cell division cycle (10-12), circadian rhythmicity (13, 14), and phenotypic plasticity (15, 16). Recent evidence suggests that several IDPs can act in a prion-like manner to create protein-based molecular memories that drive the emergence and inheritance of biological traits (17), furt...

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Section: Discussionsupporting

confidence: 80%

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Kulkarni

Jolly

Jia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

149

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“…Metastatic prostate cancer tissues (n ¼ 21) were collected from soft-tissue metastasis of patients who died from prostate cancer, as part of the Johns Hopkins Autopsy Study of lethal PCa. The clinical characteristics of the patients have been described previously (25). This study complies with the Declaration of Helsinki and was approved by the Institutional Ethics Committee.…”

Section: Patients and Samplesmentioning

confidence: 99%

“…Patients with prostate cancer were followed up from 1 to 14 years (median, 2 years). Biochemical recurrence was defined as a postoperative elevation of serum PSA (0.2 ng/mL or greater) after radical prostatectomy (25). The endpoint of the follow-up in this study was the time to biochemical recurrence.…”

Section: Patients and Samplesmentioning

confidence: 99%

Stress-Response Protein RBM3 Attenuates the Stem-like Properties of Prostate Cancer Cells by Interfering with CD44 Variant Splicing

et al. 2013

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Stress-response pathways play an important role in cancer. The cold-inducible RNA-binding protein RBM3 is upregulated in several types of cancer, including prostate cancer, but its pathogenic contributions are undetermined. RBM3 is expressed at low basal levels in human fetal prostate or in CD133 þ prostate epithelial cells (PrEC), compared with the adult prostate or CD133-PrEC, and RBM3 is downregulated in cells cultured in soft agar or exposed to stress. Notably, RBM3 overexpression in prostate cancer cells attenuated their stem celllike properties in vitro as well as their tumorigenic potential in vivo. Interestingly, either overexpressing RBM3 or culturing cells at 32 C suppressed RNA splicing of the CD44 variant v8-v10 and increased expression of the standard CD44 (CD44s) isoform. Conversely, silencing RBM3 or culturing cells in soft agar (under conditions that enrich for stem cell-like cells) increased the ratio of CD44v8-v10 to CD44s mRNA. Mechanistic investigations showed that elevating CD44v8-v10 interfered with MMP9-mediated cleavage of CD44s and suppressed expression of cyclin D1, whereas siRNA-mediated silencing of CD44v8-v10 impaired the ability of prostate cancer cells to form colonies in soft agar. Together, these findings suggested that RBM3 contributed to stem cell-like character in prostate cancer by inhibiting CD44v8-v10 splicing. Our work uncovers a hitherto unappreciated role of RBM3 in linking stress-regulated RNA splicing to tumorigenesis, with potential prognostic and therapeutic implications in prostate cancer. Cancer Res; 73(13); 4123-33. Ó2013 AACR.

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“…Inspired by this intriguing possibility, Shiraishi et al 39 devised a strategy to further explore the CTAs as potential biomarkers that can predict prostate cancer progression. We first mined publicly available microarray data on CTA expression in prostate cancer samples from the Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/ geo) in conjunction with our own data that we had previously obtained using a custom CT microarray 38 and selected a panel of candidate CTAs for investigation.…”

Section: Ctas As Potential Biomarkers To Discern Aggressive Phenotypementioning

confidence: 99%

“…Although Gleason score is believed to be one of the strongest predictors of recurrence, it tends to be subjective. Therefore, this quantitative multiplex real-time PCR assay developed by Shiraishi et al 39 could provide an objective assessment that is quantitative and consistent across institutions. Thus, this CTA-based 'gene signature' appeared to have the potential to be a 'molecular' Gleason score.…”

Section: Ctas As Potential Biomarkers To Discern Aggressive Phenotypementioning

confidence: 99%

Cancer/testis antigens: novel tools for discerning aggressive and non-aggressive prostate cancer

Shiraishi¹,

Getzenberg²,

Kulkarni³

2012

Asian J Androl

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Cancer/Testis antigens as potential predictors of biochemical recurrence of prostate cancer following radical prostatectomy

Cited by 70 publications

References 30 publications

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Stress-Response Protein RBM3 Attenuates the Stem-like Properties of Prostate Cancer Cells by Interfering with CD44 Variant Splicing

Cancer/testis antigens: novel tools for discerning aggressive and non-aggressive prostate cancer

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