Mozar Fitya, Sharma Vikas, Gorityala Shashank, Albert Jeffrey M, Xu Yan, Montano Monica M
Department of Pharmacology; Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
Endocrinology. 2022 Jan 1;163(1). doi: 10.1210/endocr/bqab236.
We have previously reported that hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the activity of ligand-bound estrogen receptor α (ERα) and the androgen receptor (AR) by disrupting the interaction between these receptors and positive transcriptional elongation factor b (P-TEFb) and attenuating RNA polymerase II (RNAPII) phosphorylation at serine 2. Functional consequences of the inhibition of transcriptional activity of ERα and AR by HEXIM1 include the inhibition of ERα- and AR-dependent gene expression, respectively, and the resulting attenuation of breast cancer (BCa) and prostate cancer (PCa) cell proliferation and growth. In our present study, we determined that HEXIM1 inhibited AKR1C3 expression in BCa and PCa cells. AKR1C3, also known as 17β-hydroxysteroid dehydrogenase (17β-HSD) type 5, is a key enzyme involved in the synthesis of 17β-estradiol (E2) and 5-dihydrotestosterone (DHT). Downregulation of AKR1C3 by HEXIM1 influenced E2 and DHT production, estrogen- and androgen-dependent gene expression, and cell proliferation. Our studies indicate that HEXIM1 has the unique ability to inhibit both the transcriptional activity of the ER and AR and the synthesis of the endogenous ligands of these receptors.
我们之前曾报道，六亚甲基双乙酰胺诱导蛋白1（HEXIM1）通过破坏这些受体与正转录延伸因子b（P-TEFb）之间的相互作用，并减弱RNA聚合酶II（RNAPII）丝氨酸2位点的磷酸化，来抑制配体结合的雌激素受体α（ERα）和雄激素受体（AR）的活性。HEXIM1对ERα和AR转录活性的抑制作用所产生的功能后果分别包括抑制ERα和AR依赖性基因表达，以及由此导致的乳腺癌（BCa）和前列腺癌（PCa）细胞增殖和生长的减弱。在我们目前的研究中，我们确定HEXIM1在BCa和PCa细胞中抑制AKR1C3的表达。AKR1C3，也称为5型17β-羟基类固醇脱氢酶（17β-HSD），是参与17β-雌二醇（E2）和5-二氢睾酮（DHT）合成的关键酶。HEXIM1对AKR1C3的下调影响了E2和DHT的产生、雌激素和雄激素依赖性基因表达以及细胞增殖。我们的研究表明，HEXIM1具有独特的能力，既能抑制ER和AR的转录活性，又能抑制这些受体的内源性配体的合成。
