KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations

Citations Over TimeTop 14% of 2018 papers

Abstract

Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75- (CD34+) and CD34-p75- (CD34-) tumor subpopulations were characterized as melanoma-propagating cells (MPC) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemoresistance. In this study, we demonstrate that CD34+ and CD34- subpopulations carrying the BRAFV600E mutation confer differential sensitivity to targeted BRAF inhibition. Through elevated KDM5B expression, melanoma cells shift toward a more drug-tolerant, CD34- state upon exposure to BRAF inhibitor or combined BRAF inhibitor and MEK inhibitor treatment. KDM5B loss or inhibition shifts melanoma cells to the more BRAF inhibitor-sensitive CD34+ state. These results support that KDM5B is a critical epigenetic regulator that governs the transition of key MPC subpopulations with distinct drug sensitivity. This study also emphasizes the importance of continuing to advance our understanding of intratumor heterogeneity and ultimately develop novel therapeutics by altering the heterogeneous characteristics of melanoma.

Related Papers

• → Epigenetic Modifiers as Game Changers for Healthy Aging(2023)8 cited
• → Relationship of cell-mediated cytotoxicity against melanoma cells to prognosis in melanoma patients(1978)41 cited
• Research and application on plant growth regulators(2008)
• Mechanism of Temperature Regulator and Application of Home Produced Regulator(2006)
• On the Replacement of Electronic Regulator in Vehicles(2007)