High-mobility-group protein 2 regulated by microRNA-127 and small heterodimer partner modulates pluripotency of mouse embryonic stem cells and liver tumor initiating cells.

High-mobility-group protein 2 (HMGB2) expression is upregulated in human liver cancer. However, little is known about its regulatory function. Here we establish HMGB2 as a new modulator of the pluripotency of mouse embryonic stem cells (ESCs). Similar to OCT4 and SOX2, HMGB2 protein is highly expressed in undifferentiated CGR8 cells, whereas it undergoes rapid decline during embryonic body (EB) formation. HMGB2 interacts with OCT4, increases protein expression of OCT4 and SOX2, and enhances their transcriptional activities. We also show that miRNA-127 is a translational repressor of HMGB2 protein expression by targeting its 3'UTR. We further elucidate a trancrptional mechanism controlling HMGB2 mRNA expression by nuclear receptor SHP and transcription factor E2F1. Diminishing HMGB2 expression by ectopic expression of miR-127 or SHP, or treatment with a small molecule inhibitor inflachromene (ICM), decreases OCT4 and SOX2 expression and facilitates CGR8 differentiation. In addition, HMGB2 is markedly induced in liver tumor initiating cells (TICs). Diminishing HMGB2 expression by shHMGB2, miR-127 or SHP impaires spheroid formation. Importantly, HMGB2 expression is elevated in various human cancers. HMGB2 acts upstream of the OCT4/SOX2 signaling to control ESCs pluripotency. Diminishing HMGB2 expression by miR-127 or SHP may provide a potential means to decrease the pluripotency of tumor initiating cells.