The human nuclear receptor (NR) superfamily consists of 48 genes that are ligand-activated transcription factors that play a key role in maintaining cellular homeostasis and in pathophysiology. NRs are important drug targets for both cancer and non-cancer endpoints as ligands for these receptors can act as agonists, antagonists or inverse agonists to modulate gene expression. With two exceptions, the classical mechanism of action of NRs involves their interactions as monomers, dimers or heterodimers with their cognate response elements (cis-elements) in target gene promoters. Several studies showed that a number of NR-regulated genes did not directly bind their corresponding cis-elements and promoter analysis identified that NR-responsive gene promoters contained GC-rich sequences that bind specificity protein 1 (Sp1), Sp3 and Sp4 transcription factors (TFs). This review is focused on identifying an important sub-set of Sp-regulated genes that are indirectly coregulated through interactions with NRs. Subsequent studies showed that many NRs directly bind Sp1 (or Sp3 and Sp4), the NR/Sp complexes bind GC-rich sites to regulate gene expression and the NR acts as a ligand-modulated nuclear cofactor. In addition, several reports show that NR-responsive genes contain cis-elements that bind both Sp TFs and NRs, and mutation of either cis-element results in loss of NR-responsive (inducible and/or basal). Regulation of these genes involves interactions between DNA-bound Sp TFs with proximal or distal DNA-bound NRs, and, in some cases, other nuclear cofactors are required for gene expression. Thus, many NR-responsive genes are regulated by NR/Sp complexes, and these genes can be targeted by ligands that target NRs and also by drugs that induce degradation of Sp1, Sp3 and Sp4.
人类核受体（NR）超家族包含48个基因，这些基因作为配体激活的转录因子，在维持细胞稳态及病理生理过程中发挥关键作用。核受体是癌症与非癌症终点的重要药物靶点，其配体可作为激动剂、拮抗剂或反向激动剂调控基因表达。除两种例外情况外，核受体的经典作用机制涉及它们以单体、二聚体或异源二聚体形式与靶基因启动子中的同源反应元件（顺式元件）相互作用。多项研究表明，部分受核受体调控的基因并不直接结合其对应的顺式元件，启动子分析发现这些核受体响应基因的启动子含有富含GC的序列，这些序列可与特异性蛋白1（Sp1）、Sp3及Sp4转录因子结合。本综述聚焦于识别一类重要的Sp调控基因亚群，这些基因通过与核受体相互作用实现间接共调控。后续研究证实，多种核受体可直接结合Sp1（或Sp3、Sp4），形成的NR/Sp复合物通过结合富含GC位点调控基因表达，此时核受体发挥配体调节型核共因子功能。此外，多项报道显示核受体响应基因的顺式元件可同时结合Sp转录因子与核受体，任一顺式元件的突变均会导致核受体响应性（诱导性和/或基础性）丧失。这类基因的调控涉及DNA结合型Sp转录因子与近端或远端DNA结合型核受体间的相互作用，某些情况下还需要其他核共因子参与基因表达。因此，大量核受体响应基因受NR/Sp复合物调控，这些基因既可作为核受体靶向配体的作用对象，也可通过诱导Sp1、Sp3和Sp4降解的药物进行靶向干预。
Activation of Genes by Nuclear Receptor/Specificity Protein (Sp) Interactions in Cancer
肿瘤(癌症)患者之家