Roles of ubiquitination and SUMOylation on prostate cancer: mechanisms and clinical implications.

The initiation and progression of human prostate cancer are highly associated with aberrant dysregulations of tumor suppressors and proto-oncogenes. Despite that deletions and mutations of tumor suppressors and aberrant elevations of oncogenes at the genetic level are reported to cause cancers, emerging evidence has revealed that cancer progression is largely regulated by posttranslational modifications (PTMs) and epigenetic alterations. PTMs play critical roles in gene regulation, cellular functions, tissue development, diseases, malignant progression and drug resistance. Recent discoveries demonstrate that ubiquitination and SUMOylation are complicated but highly-regulated PTMs, and make essential contributions to diseases and cancers by regulation of key factors and signaling pathways. Ubiquitination and SUMOylation pathways can be differentially modulated under various stimuli or stresses in order to produce the sustained oncogenic potentials. In this review, we discuss some new insights about molecular mechanisms on ubiquitination and SUMOylation, their associations with diseases, oncogenic impact on prostate cancer (PCa) and clinical implications for PCa treatment.

Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt/mTOR pathways in prostate cancer.

BACKGROUND: The intervention of advanced prostate cancer (PCa) in patients has been commonly depending on androgen deprivation therapy. Despite of tremendous research efforts, however, molecular mechanisms on AR regulation remain poorly understood, particularly for castration resistant prostate cancer (CRPC). Targeting AR and associated factors is considered an effective strategy in PCa treatment. METHODS: Human prostate cancer cells were used in this study. Manipulations of Skp2 expression were achieved by Skp2 shRNA/siRNA or overexpression of plasmids. Dual luciferase reporter assay was applied for AR activity assessment. Western blot, ubiquitination assay, immunoprecipitation, and immunofluorescence were applied to detect the proteins. RESULTS: Our results demonstrated that Skp2 directly involves the regulation of AR expression through ubiquitination-mediated degradation. Skp2 interacted with AR protein in PCa cells, and enforced expression of Skp2 resulted in a decreased level and activity of AR. By contrast, Skp2 knockdown increased the protein accumulation and activity of AR. Importantly, changes of AR contributed by Skp2 led to subsequent alterations of PSA level in PCa cells. AR ubiquitination was significantly increased upon Skp2 overexpression but greatly reduced upon Skp2 knockdown. AR mutant at K847R abrogated Skp2-mediated ubiquitination of AR. NVP-BEZ235, a dual PI3K/mTOR inhibitor, remarkably inhibited Skp2 level with a striking elevation of AR. CONCLUSIONS: The results indicate that Skp2 is an E3 ligase for proteasome-dependent AR degradation, and K847 on AR is the recognition site for Skp2-mediated ubiquitination. Our findings reveal an essential role of Skp2 in AR signaling.

Lysosome-dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer.

Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post-translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S-phase kinase-associated protein 2) catalyzes K6- and K29-linked polyubiquitination of FOXA1 for lysosomal-dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I-III, together with a strong inverse correlation (r = -0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2-FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2-Foxa1-Pcna signaling and colocalization, whereas disruption of the Skp2-Foxa1 interplay in Pten/Trp53/Skp2 triple-null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1-41 decreased tumor proliferation, SKP2:FOXA1 ratios, and colocalization. Thus, our results highlight the significance of the SKP2-FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.

KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis.

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. SIGNIFICANCE: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer.

Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer.

Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.

Translocator Protein PET Imaging in a Preclinical Prostate Cancer Model.

PURPOSE: The identification and targeting of biomarkers specific to prostate cancer (PCa) could improve its detection. Given the high expression of translocator protein (TSPO) in PCa, we investigated the use of [18F]VUIIS1008 (a novel TSPO-targeting radioligand) coupled with positron emission tomography (PET) to identify PCa in mice and to characterize their TSPO uptake. PROCEDURES: Ptenpc-/-, Trp53pc-/- prostate cancer-bearing mice (n = 9, 4-6 months old) were imaged in a 7T MRI scanner for lesion localization. Within 24 h, the mice were imaged using a microPET scanner for 60 min in dynamic mode following a retro-orbital injection of ~ 18 MBq [18F]VUIIS1008. Following imaging, tumors were harvested and stained with a TSPO antibody. Regions of interest (ROIs) were drawn around the tumor and muscle (hind limb) in the PET images. Time-activity curves (TACs) were recorded over the duration of the scan for each ROI. The mean activity concentrations between 40 and 60 min post radiotracer administration between tumor and muscle were compared. RESULTS: Tumor presence was confirmed by visual inspection of the MR images. The uptake of [18F]VUIIS1008 in the tumors was significantly higher (p < 0.05) than that in the muscle, where the percent injected dose per unit volume for tumor was 7.1 ± 1.6 % ID/ml and that of muscle was < 1 % ID/ml. In addition, positive TSPO expression was observed in tumor tissue analysis. CONCLUSIONS: The foregoing preliminary data suggest that TSPO may be a useful biomarker of PCa. Therefore, using TSPO-targeting PET ligands, such as [18F]VUIIS1008, may improve PCa detectability and characterization.

SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway.

Sirtuins are NAD+-dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway.

A functional polymorphism in the matrix metalloproteinase-2 gene promoter (-1306C/T) is associated with risk of development but not metastasis of gastric cardia adenocarcinoma.

Matrix metalloproteinase-2 (MMP-2) has been shown to play an importantrole in multiple ways to all stages of cancer initiation and development.We have reported previously a strong association between a functional single nucleotide polymorphism (-1306C/T) in the MMP2 promoter and risk of lung cancer (C. Yu et al., Cancer Res., 62: 6430-6433, 2002). This case control study was to assess the contribution of this MMP2 polymorphism to risk of development and metastasis of gastric cardia adenocarcinoma (GCA). MMP2 genotypes were determined by PCR-based denaturing high-performance liquid chromatography analysis and direct DNA sequencing in 356 patients with GCA and 789 frequency-matched controls in an ethnic Chinese population. We found that subjects with the CC genotype had >3-fold increased risk [adjusted odds ratio 3.36, 95% confidence interval 2.34-4.97] for developing GCA compared with those with the variant CT or TT genotype. Furthermore, the increased risk was found to be more pronounced in smokers and younger subjects. However, no significant association was demonstrated between the MMP2 polymorphism and risk of metastasis of the cancer at the time of diagnosis, with the odds ratio being 0.90 (95% confidence interval 0.36-2.20) for the CC genotype. These findings are consistent with our initial observation for lung cancer and further support the hypothesis that MMP2 genotype may influence individual susceptibility to the development of certain cancer.

MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo.

ARF couples with TP53 in a canonical signaling pathway to activate cellular senescence for tumor suppressive function under oncogenic insults. However, the mechanisms on aberrant elevation of ARF in cancers are still poorly understood. We previously showed that ARF (p14ARF in human and p19Arf in mouse) elevation correlates with PTEN loss and stabilizes SLUG to reduce cell adhesion in prostate cancer (PCa). Here we report that ARF is essential for MMP7 expression, E-Cadherin decrease and the anchorage loss to the extracellular matrix (ECM) in PCa in vitro and in vivo. We found that Mmp7 is aberrantly elevated in cytosol and nucleus of malignant prostate tumors of Pten/Trp53 mutant mice. Interestingly, p19Arf deficiency strikingly decreases Mmp7 levels but increases E-Cadherin in Pten/Trp53/p19Arf mice. ARF knockdown markedly reduces MMP7 in human PCa cells. Conversely, tetracycline-inducible expression of ARF increases MMP7 with a decrease of E-Cadherin in PCa cells. Importantly, MMP7 physically binds ARF to show the co-localization in nucleus. Co-expression of MMP7 and ARF promotes cell migration, and MMP7 knockdown decreases wound healing in PCa cells. Furthermore, MMP7 elevation correlates with ARF expression in advanced human PCa. Our findings reveal for the first time that the crosstalk between ARF and MMP7 in nucleus contributes to ECM network in tumor microenvironments in vivo, implicating a novel therapeutic target for advanced PCa treatment.

SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination.

Aberrant elevation of JARID1B and histone H3 lysine 4 trimethylation (H3K4me3) is frequently observed in many diseases including prostate cancer (PCa), yet the mechanisms on the regulation of JARID1B and H3K4me3 through epigenetic alterations still remain poorly understood. Here we report that Skp2 modulates JARID1B and H3K4me3 levels in vitro in cultured cells and in vivo in mouse models. We demonstrated that Skp2 inactivation decreased H3K4me3 levels, along with a reduction of cell growth, cell migration and malignant transformation of Pten/Trp53 double null MEFs, and further restrained prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, Skp2 decreased the K63-linked ubiquitination of JARID1B by E3 ubiquitin ligase TRAF6, thus decreasing JARID1B demethylase activity and in turn increasing H3K4me3. In agreement, Skp2 deficiency resulted in an increase of JARID1B ubiquitination and in turn a reduction of H3K4me3, and induced senescence through JARID1B accumulation in nucleoli of PCa cells and prostate tumors of mice. Furthermore, we showed that the elevations of Skp2 and H3K4me3 contributed to castration-resistant prostate cancer (CRPC) in mice, and were positively correlated in human PCa specimens. Taken together, our findings reveal a novel network of SKP2-JARID1B, and targeting SKP2 and JARID1B may be a potential strategy for PCa control.

Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling.

Copy-number alterations (CNA) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here, we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy-number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non-MET-amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non-Met-amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late-stage prostate cancer.

Susceptibility to gastric cardia adenocarcinoma and genetic polymorphisms in methylenetetrahydrofolate reductase in an at-risk Chinese population.

Methylenetetrahydrofolate reductase (MTHFR) plays a centralrole in converting folate to methyl donor for DNA methylation, an epigenetic modification known to be dysregulated in carcinogenesis. Our previous study revealed that MTHFR polymorphisms contribute to a great risk of esophageal cancer in a Chinese population. This case-control study was to examine the association between MTHFR polymorphisms and gastric cardia adenocarcinoma (GCA), which is also prevalent in high-risk areas of esophageal cancer and thus may share common etiological factors with esophageal cancer in this population. The study subjects were 217 patients with GCA and 468 population controls matched on sex and age. The MTHFR C677T and A1298C genotypes were detected by a PCR-based RFLP assay. It was found that subjects with the MTHFR 677TT variant genotype had a 2-fold increased risk of GCA (odds ratio, 2.04; 95% confidence interval, 1.28-3.26). Moreover, a significantly elevated risk was also seen among the MTHFR 677CT heterozygotes (odds ratio, 1.56; 95% confidence interval, 1.03-2.36). The MTHFR A1298C polymorphism had no effect on risk of GCA. These findings are generally consistent with our initial observation for esophageal cancer and suggest that the MTHFR genotype may be a determinant of GCA among this at-risk Chinese population.

Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus.

Quetiapine is a new atypical antipsychotic drug widely used in the treatment of schizophrenia and other psychotic disorders. This study examined the influence of quetiapine on the decrease of brain-derived neurotrophic factor (BDNF) expression, induced by chronic immobilization stress, in the hippocampus of the rat. Pretreatment with 10 mg/kg of quetiapine markedly attenuated the stress-induced decrease in levels of BDNF protein, as determined by Western blot analyses, and the reduction of BDNF immunoreactivity, in hippocampal pyramidal and dentate granular neurons. These results suggest that the chronic administration of quetiapine could be neuroprotective to hippocampal neurons in schizophrenia and this effect may be related to its antipsychotic effect in patients with schizophrenia.

[Lung cancer risk associated with genetic polymorphism in myeloperoxidase (-463 G/A) in a Chinese population].

OBJECTIVE: To examine the relationship between susceptibility to lung cancer among Chinese and genetic polymorphism at nucleotide -463 (G/A) in myeloperoxidase (MPO), an enzyme found in lysosomes of phagocytes and involved in the formation of hydroxyl radicals and activation of various smoking-related carcinogens. METHODS: The association of this polymorphism with lung cancer in a hospital-based case-control study of 314 patients and 320 age- and sex-matched controls was tested. The MPO genotypes were determined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). RESULTS: The allele frequency for MPO-463A was found to be 11.0% for controls, compared with 15.0% for patients. Multivariate analysis showed an increased risk for overall lung cancer in subjects having GG genotype (OR, 1.7; 95% CI, 1.2 - 2.5), however, the elevated risk was limited to squamous cell carcinoma (OR, 2.4; 95% CI, 1.4 - 3.9; n = 177) but not to adenocarcinoma (OR, 1.3; 95% CI, 0.8 - 2.1; n = 137). In addition, the risky effect of the GG genotype on squamous cell carcinoma of the lung was evident only in the smokers and those who smoked >/= 26 pack-years (OR, 20.5; 95% CI, 5.6 - 75.3) as compared with GA and AA genotypes (OR, 6.2; 95% CI, 1.7 - 22.5) but not in the nonsmokers or those who smoked < 26 pack-years. CONCLUSION: Our data support the hypothesis that -463A polymorphism in the MPO gene may reduce the susceptibility to lung cancer in the Chinese.

[Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of breast cancer].

OBJECTIVE: To investigate the association between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and risk of breast cancer among women. METHODS: Two hundred seventeen cases with breast cancer and 218 matched controls were genotyped for the MTHFR C677T and A1298C polymorphisms by PCR-RFLP methods. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression model. RESULTS: We found that the frequency of the MTHFR C677TT genotype among cases was significantly different from that among controls (32.7% vs. 24.8%; P = 0.02). The MTHFR C677TT genotype had an increased risk of breast cancer compared with the 677CC genotype (95% CI, 1.09 - 3.14). No significant association between the MTHFR C677T or A1298C polymorphism and risk of the cancer was observed. CONCLUSION: These findings suggest that 677CT polymorphism in MTHFR may be a genetic susceptibility factor for breast cancer among Chinese women.

[Association of genetic polymorphisms in the DNA repair gene XPD with risk of lung and esophageal cancer in a Chinese population in Beijing].

OBJECTIVE: XPD polymorphisms at Asp312Asn and Lys751Gln sites have been shown to modulate DNA repair capacity. The authors therefore assessed the relationship between these XPD polymorphisms and susceptibility to lung and esophageal cancer in a Chinese population via a hospital-based, case-control study. METHODS: Genotypes were determined by PCR-restriction fragment length polymorphism approaches in 383 healthy controls, 351 patients with lung cancer, and 325 patients with esophageal squamous cell carcinoma (SCC). The adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression. RESULTS: Individuals carrying at least one 312Asn variant allele (Asp/Asn and Asn/Asn genotypes) were at an increased risk for lung SCC as compared with those with the Asp/Asp genotype (OR 1.80; 95% CI: 1.10-2.93; adjusted for age, sex and smoking), but this increased risk was not observed among patients with adenocarcinoma of the lung (adjusted OR: 1.07; 95% CI: 0.55-2.08). Furthermore, stratified analysis indicated a multiplicative interaction between tobacco smoking and the variant XPD 312Asn and 751Gln alleles on risk of lung SCC. The ORs of lung SCC for the variant XPD 312Asn and 751Gln alleles with smoking>or=29 pack/year were 12.44 (95% CI: 4.97-31.17) and 10.74 (95% CI: 4.51-25.57), respectively. No significant association between the Asp312Asn or Lys751Gln polymorphism and the risk of esophageal cancer was found. CONCLUSION: The above findings indicate that the Asp312Asn and Lys751Gln polymorphisms in the XPD locus are associated with the risk of lung SCC but not lung adenocarcinoma or esophageal SCC in this Chinese population.

[Single nucleotide polymorphisms in methylenetetrahydrofolate reductase gene and susceptibility to cancer of the gastric cardia in Chinese population].

OBJECTIVE: To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism that affects DNA methylation and synthesis, and the risk of adenocarcinoma of the gastric cardia (AGC). METHODS: Genomic DNA was isolated from the peripheral lymphocytes of 205 patients with AGC and 360 age-and-sex-matched control subjects. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFR genes C6677T and A1298C and the relation between these genotypes and risk of AGC was analyzed. RESULTS: The genotype frequency of MTHFR C677CC was 35.0% among the controls and was 20.5% among the AGC patients; the genotype frequency of 677CT was 47.8% among the controls and 50.7% among the AGC patients, and the genotype frequency of 677TT was 17.2% among the controls and 28.8% among the AGC patients % (chi(2) = 17.63, P = 0.0002). The individuals with 677CT genotype or 677TT genotype had a 1.76-fold [95% confidence interval (CI), 1.13 - 2.76] or 2.97-fold (95% CI, 1.75 - 5.05) increased risk of developing AGC compared with those who had 677CC genotype. The distribution of MTHFR A1298C genotype was not significantly different between the two groups (chi(2) = 0.08, P = 0.96). The value of odd ratio (OR) in the individuals with 677CT//1298AA genotype (95% CI, 1.48 approximately 6.48), and the value of OR in the individuals with 677CT/1298CC genotype was 17.00 (95% CI, 1.26 approximately infinity; P = 0.042). CONCLUSION: Single nucleotide polymorphism in the MTHFR gene is a risk factor of carcinogenesis of AGC in the Chinese population. Although the MTHFR A1298C polymorphism was not associated with AGC, The risk of developing AGC in the individuals with MTHFR677CT/1298CC was 17 times higher than that in the individuals with MTHFR677CC/1298AA, thus showing that a joint effect exists between the MTHFR 677 and 1298 polymorphisms on the risk of AGC.

Regulation of Androgen Receptor by E3 Ubiquitin Ligases: for More or Less.

Prostate cancer (PCa) primarily depends on the dysregulations of androgen receptor (AR) signaling pathway for the initiation and growth as well as recurrence after chemotherapy [1]. Androgen deprivation therapy (ADT) effectively alleviates symptoms of the malignancy to arrest further growth of primary tumors or progression of metastasis in patients with advanced PCa. However, relapse occurs in many patients after a short period, and PCa cells eventually become insensitive to ADT - termed castration resistant prostate cancer (CRPC) [2, 3]. Tremendous advancements have been achieved to decipher the mechanisms on AR signaling, and the ubiquitination machinery contributes to PCa directly or indirectly by either promotion of AR transcriptional activity or degradation of AR protein levels. The recent report reveals that SKP2 regulates AR protein through ubiquitin-mediated proteasomal degradation, highlighting the role of SKP2 in AR signaling. Given the pivotal roles of AKT and SKP2 in cancers, the differential mechanisms of AR ubiquitination by various E3 ligases hold valuable significance and beneficial implications for PCa control.

Crosstalk between nuclear MET and SOX9/ß-catenin correlates with castration-resistant prostate cancer.

Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, ß-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and ß-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/ß-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.

Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis.

SLUG represses E-cadherin to promote epithelial-mesenchymal transition (EMT) in various cancers. Mechanisms that regulate SLUG/E-cadherin pathway remain poorly understood, especially during tumorigenesis in vivo. Here we report that p19(Arf) (p14(ARF) in human) stabilizes Slug to inhibit E-cadherin in prostate cancer mouse models. Inactivation of p19(Arf) reduces Slug levels, resulting in increased E-cadherin expression and delaying the onset and progression of prostate cancer in Pten/Trp53 double null mice. Mechanistically, p14(ARF) stabilizes SLUG through increased sumoylation at lysine residue 192. Importantly, levels of SLUG and p14(ARF) are positively correlated in human prostate cancer specimens. These data demonstrated that ARF modulates the SLUG/E-cadherin signaling axis for augmenting prostate tumorigenesis in vivo, revealing a novel paradigm where the oncogenic functions of SLUG require ARF to target E-cadherin in prostate cancer. Collectively, our findings further support that ARF has dual tumor suppressive/oncogenic roles in cancers in a context-dependent manner.