gsk-j4 and Colorectal-Neoplasms

Tumor-initiating cells (TICs) maintain heterogeneity within tumors and seed metastases at distant sites, contributing to therapeutic resistance and disease recurrence. In colorectal cancer (CRC), strategy that effectively eradicates TICs and is of potential value for clinical use still remains in need.

Topics: Animals; Benzazepines; Cell Line, Tumor; Colorectal Neoplasms; Gene Expression Profiling; HCT116 Cells; Histone Demethylases; HT29 Cells; Humans; Jumonji Domain-Containing Histone Demethylases; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells; Pyrimidines

Histone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Benzazepines; Biphenyl Compounds; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; HCT116 Cells; Histone Demethylases; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Male; Methylation; Mice; Mice, Nude; Middle Aged; Morpholines; Oxaliplatin; Prognosis; Pyridones; Pyrimidines; Receptor, Notch2; Signal Transduction; Tumor Burden; Up-Regulation; Xenograft Model Antitumor Assays