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Ikaros Modulates Cholesterol Uptake: A Link between Tumor Suppression and Differentiation

¹ Departments of Medicine and ² Pathology, University Health Network; ³ Division of Applied Molecular Oncology, Ontario Cancer Institute, Toronto, Ontario, Canada

Requests for reprints: Sylvia L. Asa, Ontario Cancer Institute, 610 University Avenue #8-209, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2099; Fax: 416-340-5517; E-mail: sylvia.asa{at}uhn.on.ca.

Key Words: cholesterol • metabolism • stem cells

Ikaros is a transcription factor that directs lymphoid lineage commitment and pituitary neuroendocrine cell expansion and function. Here, we show that Ikaros regulates the low-density lipoprotein receptor (LDL-R) to alter metabolism in pituitary corticotroph cells. The DNA-binding Ikaros isoform Ik1 binds and enhances activity of the LDL-R promoter. Ik1 decreases methylation and increases acetylation of histone H3 (Lys⁹) at the LDL-R promoter. Confocal microscopy and quantitative fluorometry show enhanced LDL endocytosis in Ik1-transfected cells that exhibit abundant endoplasmic reticulum, large Golgi complexes, and prominent secretory granule formation, consistent with more robust cholesterol incorporation into functionally relevant membrane-rich organelles. Consistent with these data, LDL-R^–/– mice, like Ik^–/– mice, have decreased circulating levels of adrenocorticotropic hormone. These findings expand the repertoire of Ikaros actions to include regulation of the cholesterol uptake metabolic pathway with therapeutic implications for lipid-modifying drugs in Ikaros-associated cancers. [Cancer Res 2008;68(10):3715–23]