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Top (most significant) 200 up-regulated gene sets enriched in JARID1Bhigh vs. G0-like LNT14 cells.

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 JARID1Bhigh fraction of cells with stem cell–like function. JARID1Bhigh 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 JARID1Bhigh 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 JARID1Bhigh cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538–49. ©2016 AACR.

Characterization of G0-like OSCC cells (S1); Characterization of JARID1Bhigh OSCC cells (S2); Functional analysis of JARID1Bhigh OSCC cells (S3); Molecular analysis of G0-like and JARID1Bhigh OSCC cells (S4); Characterization of G0-like and EGFPhigh fractions under normal and JARID1B-depleted conditions (S5); Activation and inhibition of PI3K-Akt signaling pathway in OSCC cells (S6).