Aldehyde dehydrogenase 1B1 (ALDH1B1) has been correlated with colorectal tumorigenesis and is considered a potential biomarker for colon cancer. Its expression has been associated with attenuation of the cell cycle in the G2/M phase and resistance to DNA damaging agents. The present study examines the role of ALDH1B1 in DNA damage response (DDR) in human colorectal adenocarcinoma. To this end, we utilized an isogenic HT29 cell line pair differing in the expression of ALDH1B1. The overexpression of ALDH1B1 was related to the translational upregulation of the total and phosphorylated (at ser15) p53. Comet and apoptosis assays revealed that the expression of ALDH1B1 protected HT29 cells from etoposide-induced DNA damage as well as apoptosis, and its overexpression led to increased constitutive phosphorylation of H2AX (at ser139). Furthermore, the expression profile of a variety of DNA damage signaling (DDS)-related genes was investigated by utilizing the RT2 profiler™ PCR array. Our results demonstrated that ALDH1B1 triggered a transcriptional activation of several DNA repair-related genes (MRE11A, PMS1, RAD18 and UNG). Finally, Spearman’s rank correlation coefficient analysis in 531 publicly available colorectal adenocarcinoma clinical samples indicated the statistically significant positive correlation between ALDH1B1 and DDR and repair genes or proteins, such as APEX1, FEN1, MPG, UNG, XRCC1, DDB1, XPC, CIB1, MRE11, PRKDC, RAD50, RAD21, TP53BP1, XRCC6 and H2AX. Collectively, our results suggest that ALDH1B1 may play an essential role in the DDR and DNA repair processes. Further studies on ALDH1B1 will elucidate its precise role in DDR.

Silibinin, a diastereoisomeric mixture extracted from Silybum marianum L, with established anti-prostate cancer activity, has been associated with considerable anti-neoplastic ability, in a variety of human cancer types, through interference with the epigenetic machinery. In prostate carcinoma (PCa), high expression of polycomb repressive complex 1 (PRC1) and 2 (PRC2) members, that belong to polycomb group (PcG) proteins, is associated with transcriptional silencing of tumor suppressor genes through histone modifications and chromatin condensation. Our previous results revealed that silibinin reduced the expression levels of PRC2 complex members (EZH2, EED, SUZ12), an ability accompanied by increased H3K27me3 marks. In the current report, treatment of DU145 and PC3 prostate cancer cells with clinically-achievable concentrations (25-75μg/mL) of silibinin, resulted in reduced protein expression levels of PRC1 complex members (RING1a, RING1b and BMI1), in a dose-dependent manner, as obtained from western blot analysis. Next, human epigenetic chromatin modification enzymes-focused DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR) analyses, revealed that silibinin modulated differentially the gene expression levels of important enzymes, related with the pathophysiology of the disease, that function at the epigenetic level. Specifically, significant alterations were observed in the expression profile of enzymes associated with gene expression regulation through modification of chromatin configuration, including family members of: i) histone methyltransferases, ii) histone acetyl-transferases, iii) histone demethylases and iv) histone deacetylases along with enzymes inducing gene silencing (via DNA methylation) and regulation of cell cycle progression. Our results suggest that the anticancer activity of silibinin could be partially mediated by the disruption of central processes in chromatin configuration-remodeling and alteration of enzymes of the epigenomic landscape that regulate prostate cancer progression.