title: Combined transcriptome studies identify AFF3 as a mediator of the oncogenic effects of β-catenin in adrenocortical carcinoma.
abstract: Adrenocortical cancer (ACC) is a very aggressive tumor, and genomics studies demonstrate that the most frequent alterations of driver genes in these cancers activate the Wnt/β-catenin signaling pathway. However, the adrenal-specific targets of oncogenic β-catenin-mediating tumorigenesis have not being established. A combined transcriptomic analysis from two series of human tumors and the human ACC cell line H295R harboring a spontaneous β-catenin activating mutation was done to identify the Wnt/β-catenin targets. Seven genes were consistently identified in the three studies. Among these genes, we found that AFF3 mediates the oncogenic effects of β-catenin in ACC. The Wnt response element site located at nucleotide position -1408 of the AFF3 transcriptional start sites (TSS) mediates the regulation by the Wnt/β-catenin signaling pathway. AFF3 silencing decreases cell proliferation and increases apoptosis in the ACC cell line H295R. AFF3 is located in nuclear speckles, which play an important role in RNA splicing. AFF3 overexpression in adrenocortical cells interferes with the organization and/or biogenesis of these nuclear speckles and alters the distribution of CDK9 and cyclin T1 such that they accumulate at the sites of AFF3/speckles. We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing.
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: L
authors.initials: L
authors.lastname: Lefèvre
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: H
authors.initials: H
authors.lastname: Omeiri
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: L
authors.initials: L
authors.lastname: Drougat
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hantel
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: M
authors.initials: M
authors.lastname: Giraud
authors.affiliation: 1] Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand Cedex 1, France [2] CNRS, UMR 6293, GReD, Aubière Cedex, France [3] Inserm, U1103, GReD, Aubière Cedex, France.
authors.forename: P
authors.initials: P
authors.lastname: Val
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: S
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: K
authors.initials: K
authors.lastname: Perlemoine
authors.affiliation: 1] Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Plateforme Génomique, Paris, France [2] Inserm, U1024, Paris, France [3] CNRS, UMR 8197, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Blugeon
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Beuschlein
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: M
authors.initials: M
authors.lastname: Rizk-Rabin
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France [4] Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: B
authors.initials: B
authors.lastname: Ragazzon