Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA.

This study reports a histone deacetylation-independent mechanism whereby histone deacetylase (HDAC) inhibitors sensitize prostate cancer cells to DNA-damaging agents by targeting Ku70 acetylation. Ku70 represents a crucial component of the nonhomologous end joining repair machinery for DNA double-strand breaks (DSB). Our data indicate that pretreatment of prostate cancer cells with HDAC inhibitors (trichostatin A, suberoylanilide hydroxamic acid, MS-275, and OSU-HDAC42) led to increased Ku70 acetylation accompanied by reduced DNA-binding affinity without disrupting the Ku70/ Ku80 heterodimer formation. As evidenced by increased Ser 139 -phosphorylated histone H2AX (;H2AX), impaired Ku70 function diminished cellular capability to repair DNA DSBs induced by bleomycin, doxorubicin, and etoposide, thereby enhancing their cell-killing effect. This sensitizing effect was most prominent when cells were treated with HDAC inhibitors and DNA-damaging agents sequentially. Mimicking acetylation was done by replacing K282, K317, K331, K338, K539, or K542 with glutamine via site-directed mutagenesis, which combined with computer docking analysis was used to analyze the role of these lysine residues in the interactions of Ku70 with DNA broken ends. Mutagenesis of K282, K338, K539, or K542 suppressed the activity of Ku70 to bind DNA, whereas mutagenesis of K317 or K331 with glutamine had no significant effect. Moreover, overexpression of K282Q or K338Q rendered DU-145 cells more susceptible to the effect of DNA-damaging agents on ;H2AX formation and cell killing. Overall, the ability of HDAC inhibitors to regulate cellular ability to repair DNA damage by targeting Ku70 acetylation underlies the viability of their combination with DNAdamaging agents as a therapeutic strategy for prostate cancer.

A penalized likelihood (PL) method for structural equation modeling (SEM) was proposed as a methodology for exploring the underlying relations among both observed and latent variables. Compared to the usual likelihood method, PL includes a penalty term to control the complexity of the hypothesized model. When the penalty level is appropriately chosen, the PL can yield an SEM model that balances the model goodness-of-fit and model complexity. In addition, the PL results in a sparse estimate that enhances the interpretability of the final model. The proposed method is especially useful when limited substantive knowledge is available for model specifications. The PL method can be also understood as a methodology that links the traditional SEM to the exploratory SEM (Asparouhov & Muthén in Struct Equ Model Multidiscipl J 16:397-438, 2009). An expectation-conditional maximization algorithm was developed to maximize the PL criterion. The asymptotic properties of the proposed PL were also derived. The performance of PL was evaluated through a numerical experiment, and two real data illustrations were presented to demonstrate its utility in psychological research.