E2F1-mediated human POMC expression in ectopic Cushing's syndrome

Takako Araki, Ning Ai Liu, Yukiko Tone, Daniel Cuevas-Ramos, Roy Heltsley, Masahide Tone, Shlomo Melmed

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)857-870
Number of pages14
JournalEndocrine-related cancer
Volume23
Issue number11
DOIs
StatePublished - Nov 2016

Fingerprint

Pro-Opiomelanocortin
Cushing Syndrome
Adrenocorticotropic Hormone
Tumor Cell Line
Corticotrophs
Pituitary ACTH Hypersecretion
Neoplasms
DNA
Pituitary Neoplasms
Ectopic Gene Expression
Genetic Promoter Regions
Hydrocortisone
Phosphorylation
Gene Expression
Cell Line
Messenger RNA
Therapeutics

Keywords

  • E2F1
  • Ectopic Cushing's syndrome
  • Proopiomelanocortin (POMC)
  • Ser-337 E2F1

Cite this

Araki, T., Liu, N. A., Tone, Y., Cuevas-Ramos, D., Heltsley, R., Tone, M., & Melmed, S. (2016). E2F1-mediated human POMC expression in ectopic Cushing's syndrome. Endocrine-related cancer, 23(11), 857-870. https://doi.org/10.1530/ERC-16-0206

E2F1-mediated human POMC expression in ectopic Cushing's syndrome. / Araki, Takako; Liu, Ning Ai; Tone, Yukiko; Cuevas-Ramos, Daniel; Heltsley, Roy; Tone, Masahide; Melmed, Shlomo.

In: Endocrine-related cancer, Vol. 23, No. 11, 11.2016, p. 857-870.

Research output: Contribution to journalArticle

Araki, T, Liu, NA, Tone, Y, Cuevas-Ramos, D, Heltsley, R, Tone, M & Melmed, S 2016, 'E2F1-mediated human POMC expression in ectopic Cushing's syndrome', Endocrine-related cancer, vol. 23, no. 11, pp. 857-870. https://doi.org/10.1530/ERC-16-0206
Araki T, Liu NA, Tone Y, Cuevas-Ramos D, Heltsley R, Tone M et al. E2F1-mediated human POMC expression in ectopic Cushing's syndrome. Endocrine-related cancer. 2016 Nov;23(11):857-870. https://doi.org/10.1530/ERC-16-0206
Araki, Takako ; Liu, Ning Ai ; Tone, Yukiko ; Cuevas-Ramos, Daniel ; Heltsley, Roy ; Tone, Masahide ; Melmed, Shlomo. / E2F1-mediated human POMC expression in ectopic Cushing's syndrome. In: Endocrine-related cancer. 2016 ; Vol. 23, No. 11. pp. 857-870.
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