SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner
AbstractLuminal breast cancers express estrogen (ER) and progesterone (PR) receptors, and respond to endocrine therapies. However, some ER+PR+ tumors display intrinsic or acquired resistance, possibly related to PR. Two PR isoforms, PR-A and PR-B, regulate distinct gene subsets that may differentially influence tumor fate. A high PR-A:PR-B ratio is associated with poor prognosis and tamoxifen resistance. We speculate that excessive PR-A marks tumors that will relapse early. Here we address mechanisms by which PR-A regulate transcription, focusing on SUMOylation. We use receptor mutants and synthetic promoter/reporters to show that SUMOylation deficiency or the deSUMOylase SENP1 enhance transcription by PR-A, independent of the receptors’ dimerization interface or DNA binding domain. De-SUMOylation exposes the agonist properties of the antiprogestin RU486. Thus, on synthetic promoters, SUMOylation functions as an independent brake on transcription by PR-A. What about PR-A SUMOylation of endogenous human breast cancer genes? To study these, we used gene expression profiling. Surprisingly, PR-A SUMOylation influences progestin target genes differentially, with some upregulated, others down-regulated, and others unaffected. Hormone-independent gene regulation is also PR-A SUMOylation dependent. Several SUMOylated genes were analyzed in clinical breast cancer database. In sum, we show that SUMOylation does not simply repress PR-A. Rather it regulates PR-A activity in a target selective manner including genes associated with poor prognosis, shortened survival, and metastasis. View Full-Text
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Abdel-Hafiz, H.A.; Dudevoir, M.L.; Perez, D.; Abdel-Hafiz, M.; Horwitz, K.B. SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner. Diseases 2018, 6, 5.
Abdel-Hafiz HA, Dudevoir ML, Perez D, Abdel-Hafiz M, Horwitz KB. SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner. Diseases. 2018; 6(1):5.Chicago/Turabian Style
Abdel-Hafiz, Hany A.; Dudevoir, Michelle L.; Perez, Daniel; Abdel-Hafiz, Mohamed; Horwitz, Kathryn B. 2018. "SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner." Diseases 6, no. 1: 5.
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