Ikaros modulates cholesterol uptake: a link between tumor suppression and differentiation.
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 (Lys(9)) 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.
Loeper
Siobhan
S
Departments of Medicine and Pathology, University Health Network, Ontario Cancer Institute, Toronto, Ontario, Canada.
Asa
Sylvia L
SL
Ezzat
Shereen
S
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*
C497239:IKZF1 protein, human; D011973:Receptors, LDL; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D000324:Adrenocorticotropic Hormone; D002784:Cholesterol