Data from JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers

The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1B^high fraction of cells with stem cell–like function. JARID1B^high cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3K pathway activation. They were distinguished from a fraction in a G₀-like cell-cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G₀-like cells lacked conventional CSC markers but were primed to acquire stem cell–like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1B^high cells but expanding the G₀-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G₀-like subset during targeted depletion of JARID1B^high cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538–49. ©2016 AACR.