E2F1-mediated human POMC expression in ectopic Cushing's syndrome
E2F1-mediated human POMC expression in ectopic Cushing's syndrome
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DOI：
10.1530/erc-16-0206
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发表时间：
2016-11-01
影响因子：
3.9
通讯作者：
Melmed, Shlomo
中科院分区：
文献类型：
--
作者：
Araki, Takako;Liu, Ning-Ai;Melmed, Shlomo
库欣综合征是由垂体促肾上腺皮质激素瘤（库欣病）或非垂体肿瘤（异位库欣综合征）产生的促肾上腺皮质激素（ACTH）分泌过多引起的。异位库欣综合征的皮质功能亢进是严重的，并且没有确定的治疗副肿瘤性ACTH过量。我们的目的是通过阐明非垂体瘤细胞和异位库欣综合征患者细胞系中人促肾上腺皮质激素前体POMC（阿黑皮素原）和促肾上腺皮质激素产生的转录调控来确定亚细胞治疗靶点。我们发现，异位hPOMC转录独立于垂体特异性Tpit/Pitx 1进行，并证明了一种新的E2 F1介导的转录机制调节hPOMC。我们鉴定了与hPOMC启动子近端区域（-42至+68）结合的E2 F1簇，其DNA结合活性由Ser-337的磷酸化决定。癌细胞中的hPOMC mRNA表达通过E2 F1及其异源二聚体伴侣DP 1的共表达而上调（高达40倍）。E2 F1活性的直接和间接抑制剂通过改变异位库欣细胞系和原发性肿瘤细胞中E2 F1 DNA结合活性来抑制hPOMC基因表达和ACTH，并且还抑制异种移植小鼠中的副肿瘤ACTH和皮质醇水平。E2 F1介导的hPOMC转录是抑制异位库欣综合征ACTH产生的潜在靶点。
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.