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Tumor-Derived Ikaros 6 Acetylates the Bcl-XL Promoter to Up-Regulate a Survival Signal in Pituitary Cells

Department of Medicine (S.E., X.Z.), Mount Sinai Hospital and University of Toronto; Department of Pathology (S.F., S.L.A.), University Health Network and University of Toronto; and The Freeman Centre for Endocrine Oncology and The Ontario Cancer Institute (S.E., X.Z., S.F., S.L.), Toronto, Ontario, Canada M5G 2M9

Address all correspondence and requests for reprints to: Dr. Sylvia. L. Asa, University Health Network, 610 University Avenue, 8-318, Toronto, Ontario, Canada M5G 2M9. E-mail: sylvia.asa{at}uhn.on.ca.

We reported the expression of the lymphoid zinc finger transcription factor Ikaros (Ik) in the endocrine pituitary gland, where the usual isoforms, Ik1 and Ik2, are thought to play multiple physiological roles. The gene is alternatively spliced to yield a dominant negative isoform, Ik6, in nearly half of human pituitary tumors. We show here that the tumor-specific truncated Ik6 isoform promotes pituitary tumor AtT20 corticotroph and GH4 mammosomatotroph cell growth, evidenced by increased S-phase entry, colony formation in soft agar, and growth of xenografts in vivo. Ik6-mediated cell growth was associated with enhanced protection against apoptosis and up-regulation of the antiapoptotic factor Bcl-XL but not the related Bcl-2 family member. The effect of Ik6 on Bcl-XL induction was not reproduced by small interfering RNA-mediated Ik-down-regulation, indicating that this effect is not mediated entirely by disruption of Ik1 action. In cotransfection studies, Ik1 attenuated and Ik6 enhanced Bcl-XL promoter activity. The effect of Ik6 was mimicked by histone deacetylation inhibition but not by methylation inhibition. Furthermore, chromatin immunoprecipitation confirmed the ability of Ik6 to selectively acetylate histone 3 sites but not influence methylation of the Bcl-XL promoter. Thus, the contribution of Ik6 to tumor pathogenesis involves up-regulation of an antiapoptotic signal generated through selective acetylation of the Bcl-XL promoter.

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