SOX4 is activated by C-MYC in prostate cancer.

Although MYC proto-oncogene (C-MYC) amplification has been consistently reported to be a potential marker for prostate cancer (PCa) progression and prognosis, the clinicopathological and prognostic significance of C-MYC protein expression remains controversial. Overexpression of SOX4 has been shown to play important roles in multiple cancers including PCa. However, the link between these two critical genetic aberrations is unclear. In the current study, we showed that C-MYC was overexpressed in 16.2% (17/105) of Chinese patients with localized PCa. Overexpression of C-MYC was significantly associated with high Gleason scores (P = 0.012) and high Ki67 labeling index (P = 0.005). C-MYC overexpression was correlated with cancer-related mortality and suggested to be an unfavorable prognostic factor in Chinese PCa patients (P = 0.018). Overexpression of C-MYC is associated with SOX4 overexpression in PCa tissues. Notably, SOX4 is a direct target gene of C-MYC; C-MYC activates SOX4 expression via binding to its promoter. In addition, Co-IP analysis demonstrated a physical interaction between C-MYC and SOX4 protein in PCa cells. Clinically, C-MYC+/SOX4+ characterized poor prognosis in a subset of PCa patients. In total, C-MYC overexpression may contribute to PCa progression by activating SOX4. Our findings highlight an important role of C-MYC/SOX4 in PCa progression in a subset of PCa patients.

CUL4B/miR-33b/C-MYC axis promotes prostate cancer progression.

BACKGROUND: Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, is overexpressed in many types of solid tumors and contributes to epigenetic silencing of tumor suppressors. However, its clinical significance and underlying molecular mechanisms in prostate cancer (PCa) remain unknown. METHODS: The clinical significance of CUL4B in PCa was characterized by in silico method. RT-qPCR and Western blot were used to study the transcript and protein expression levels of CUL4B and C-MYC. Bioinformatics tools, chromatin immunoprecipitation (ChIP) and luciferase reporter assay were utilized to identify and characterize the microRNAs (miRNAs) regulated by CUL4B. The biological function of CUL4B and miR-33b-5p was evaluated by MTS, transwell, and wound healing assays, accordingly. RESULTS: CUL4B is significantly overexpressed in PCa tissues compared with benign prostatic tissues and its overexpression is correlated with poor prognosis. CUL4B promotes proliferation and aggressiveness of PCa cells in vitro. Mechanistically, we demonstrate that CUL4B upregulates the expression of C-MYC at post-transcriptional level through epigenetic silencing of miR-33b-5p. Importantly, CUL4B-induced oncogenic activity in PCa by targeting C-MYC is repressed by miR-33b-5p. CONCLUSIONS: Our results suggested a novel CUL4B/miR-33b/C-MYC axis implicated in PCa cell growth and progression. This might provide novel insight into how CUL4B contributed to PCa aggressiveness and progression.

TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12.

Breast cancer (BC) is among the most common malignant diseases and metastasis is the handcuff of treatment. Cancer metastasis is a multistep process associated with the epithelial-mesenchymal transition (EMT) program. Several studies have demonstrated that transcriptional repressor GATA binding 1 (TRPS1) played important roles in development and progression of primary BC. In this study we sought to identify the mechanisms responsible for this function of TRPS1 in the continuum of the metastatic cascade. Here we described that TRPS1 was significantly associated with BC metastasis using public assessable datasets. Clinically, loss of TRPS1 expression in BC was related to higher histological grade. In vitro functional study and bioinformatics analysis revealed that TRPS1 inhibited cell migration and EMT in BC. Importantly, we identified SUZ12 as a novel target of TRPS1 related to EMT program. ChIP assay demonstrated TRPS1 directly inhibited SUZ12 transcription by binding to the SUZ12 promoter. Loss of TRPS1 resulted in increased SUZ12 binding and H3K27 tri-methylation at the CDH1 promoter and repression of E-cadherin. In all, our data indicated that TRPS1 maintained the expression of E-cadherin by inhibiting SUZ12, which might provide novel insight into how loss of TRPS1 contributed to BC progression.

IDH1R132H Promotes Malignant Transformation of Benign Prostatic Epithelium by Dysregulating MicroRNAs: Involvement of IGF1R-AKT/STAT3 Signaling Pathway.

Risk stratification using molecular features could potentially help distinguish indolent from aggressive prostate cancer (PCa). Mutations in isocitrate dehydrogenase (IDH) acquire an abnormal enzymatic activity, resulting in the production of 2-hydroxyglutarate and alterations in cellular metabolism, histone modification, and DNA methylation. Mutant IDH1 has been identified in various human malignancies, and IDH1R132H constituted the vast majority of mutational events of IDH1. Most recent studies suggested that IDH1 mutations define a methylator subtype in PCa. However, the function of IDH1R132H in PCa development and progression is largely unknown. In this study, we showed that the prevalence of IDH1R132H in Chinese PCa patients is 0.6% (2/336). Of note, IDH1R132H-mutant PCa patients lacked other canonical genomic lesions (e.g., ERG rearrangement, PTEN deletion) that are common in most other PCa patients. The in vitro experiment suggested that IDH1R132H can promote proliferation of benign prostate epithelial cell RWPE-1 when under the situation of low cytokine. It could also promote migration capacity of RWPE-1 cells. Mechanistically, IDH1R132H was an important regulator of insulin-like growth factor 1receptor (IGF1R) by downregulating a set of microRNAs (miR-141-3p, miR-7-5p, miR-223-3p). These microRNAs were repressed by the alteration of epigenetic modification to decrease the enrichment of active marker H3K4me3 or to increase repressive marker H3K27me3 at their promoters. Collectively, we proposed a novel model for an IDH1R132H-microRNAs-IGF1R regulatory axis, which might provide insight into the function of IDH1R132H in PCa development.

PADI2-Mediated Citrullination Promotes Prostate Cancer Progression.

Onset of castration-resistance prostate cancer (CRPC) after long-term androgen deprivation therapy remains a major obstacle in the treatment of prostate cancer. The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that PADI2 is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell-cycle progression of prostate cancer cells, and PADI2 promoted proliferation of prostate cancer cells under androgen-deprived or castration conditions in vitro and in vivo Cytoplasmic PADI2 protected the androgen receptor (AR) against proteasome-mediated degradation and facilitated AR binding to its target genes after nuclear translocation and citrullination of histone H3 amino acid residue R26. In contrast, mutant PADI2 D180A failed to affect AR stability, nuclear translocation, or transcriptional activity. PADI2 mediated AR control in a manner dependent on its enzymatic activity and nuclear localization, as correlated with increased histone H3 citrullination. Notably, coadministration of the PADI inhibitor Cl-Amidine and the AR signaling inhibitor enzalutamide synergized in inhibiting CRPC cell proliferation in vitro and tumor growth in vivo Overall, our results establish PADI2 as a key mediator for AR in prostate cancer progression, especially CRPC, and they suggest PADI as novel therapeutic targets in this disease setting. Cancer Res; 77(21); 5755-68. ©2017 AACR.