Increased expression of NuSAP in recurrent prostate cancer is mediated by E2F1

Abstract

Increasing evidence suggests that prostate cancer is over diagnosed and over treated, and prognostic biomarkers would aid in treatment selection. To define prognostic biomarkers for aggressive prostate cancer, we carried out gene expression profiling of 98 prostate tumors and 52 benign adjacent prostate tissue samples with detailed clinical annotation. We identified 28 transcripts significantly associated with recurrence after radical prostatectomy including NuSAP, a protein that binds DNA to the mitotic spindle. Elevated NuSAP transcript levels were associated with poor outcome in 2 independent prostate cancer gene expression datasets. To characterize the role and regulation of NuSAP in prostate cancer, we studied the expression of NuSAP in the LNCaP and PC3 human prostate cancer cell lines. Post-transcriptional silencing of the NuSAP gene severely hampered the ability of PC3 to invade and proliferate in vitro. The promoter region of the NuSAP gene contains 2 CCAAT boxes and binding sites for E2F. Transient transfection of an E2F1 cDNA and 431 bp of the NuSAP promoter demonstrated E2F1 as an important regulator of expression. Deletion of the E2F binding site at nt −246 negated the effects of E2F1 on NuSAP expression. Electrophoretic mobility shift assays demonstrated that nuclear extracts of cells over-expressing E2F1 bound directly to the E2F binding site in the NuSAP promoter region. Finally, immunohistochemistry showed a strong correlation between E2F1 and NuSAP expression in human prostate cancer samples. NuSAP is a novel biomarker for prostate cancer recurrence after surgery and its over-expression appears to be driven in part by E2F1 activation.

The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone

“…The Gulzar dataset (Gulzar et al, 2013) suggests that PCa recurrence is higher in patients with low PMEPA1 expression, compared to those with high PMEPA1 (Fig 3F). Despite the separation between the populations after 2 years, the difference was not significant, which could be due to the small number of patients (n = 67).…”

Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

“…In addition, mitotic dysfunction by deregulated E2F1 and the consequent onset of oncogenesis are also emerging. E2F1 also induces increased expression of the mitotic proteins PTTG1 and NuSAP in pituitary and prostate tumors, respectively (54,55). Defects in SAC function may result in CIN and aneuploidy, which are hallmarks of cancer (22,23).…”

AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis

“…In a relevant study, a Kaplan-Meier plot revealed the significant association between higher WHSC1 expression and disease relapse in 2 separate patient cohorts (using data sets GSE21032 and GSE40272; Figure 1B and refs. 4,39). To further assess the clinical relevance of WHSC1 in PCa, we performed IHC staining with a validated antibody against WHSC1 on an Asian radical prostatectomy cohort (40), a tumor tissue microarray (TMA) composed of 118 patient specimens (Supplemental Table 2).…”