title: E2F1-mediated human POMC expression in ectopic Cushing's syndrome.
abstract: Cushing's syndrome is caused by excessive adrenocorticotropic hormone (ACTH) secretion derived from pituitary corticotroph tumors (Cushing disease) or from non-pituitary tumors (ectopic Cushing's syndrome). Hypercortisolemic features of ectopic Cushing's syndrome are severe, and no definitive treatment for paraneoplastic ACTH excess is available. We aimed to identify subcellular therapeutic targets by elucidating transcriptional regulation of the human ACTH precursor POMC (proopiomelanocortin) and ACTH production in non-pituitary tumor cells and in cell lines derived from patients with ectopic Cushing's syndrome. We show that ectopic hPOMC transcription proceeds independently of pituitary-specific Tpit/Pitx1 and demonstrate a novel E2F1-mediated transcriptional mechanism regulating hPOMC We identify an E2F1 cluster binding to the proximal hPOMC promoter region (-42 to +68), with DNA-binding activity determined by the phosphorylation at Ser-337. hPOMC mRNA expression in cancer cells was upregulated (up to 40-fold) by the co-expression of E2F1 and its heterodimer partner DP1. Direct and indirect inhibitors of E2F1 activity suppressed hPOMC gene expression and ACTH by modifying E2F1 DNA-binding activity in ectopic Cushing's cell lines and primary tumor cells, and also suppressed paraneoplastic ACTH and cortisol levels in xenografted mice. E2F1-mediated hPOMC transcription is a potential target for suppressing ACTH production in ectopic Cushing's syndrome.
authors.forename: Takako
authors.initials: T
authors.lastname: Araki
authors.forename: Ning-Ai
authors.initials: NA
authors.lastname: Liu
authors.affiliation: Pituitary CenterCedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tone
authors.affiliation: Pituitary CenterCedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cuevas-Ramos
authors.affiliation: Pituitary CenterCedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Heltsley
authors.affiliation: Pituitary CenterCedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Masahide
authors.initials: M
authors.lastname: Tone
authors.affiliation: Pituitary CenterCedars-Sinai Medical Center, Los Angeles, California, USA melmed@csmc.edu.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D000182:ACTH Syndrome, Ectopic / Q000235:genetics*; D049913:ACTH-Secreting Pituitary Adenoma / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002276:Carcinoid Tumor / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003480:Cushing Syndrome / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D011333:Pro-Opiomelanocortin
keywords: E2F1; Ser-337 E2F1; ectopic Cushing’s syndrome; proopiomelanocortin (POMC)