Safe Stephen, Farkas Evan, Hailemariam Amanuel E, Oany Arafat Rahman, Sivaram Gargi, Tsui Wai Ning Tiffany
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA.
Cancers (Basel). 2025 Jan 17;17(2):284. doi: 10.3390/cancers17020284.
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）超家族由48个基因组成，这些基因是配体激活的转录因子，在维持细胞稳态和病理生理学中起关键作用。NR是癌症和非癌症终点的重要药物靶点，因为这些受体的配体可以作为激动剂、拮抗剂或反向激动剂来调节基因表达。除了两个例外，NR的经典作用机制涉及其作为单体、二聚体或异二聚体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，许多受NR调节的基因并不直接与其相应的顺式元件结合，启动子分析表明，NR反应性基因启动子含有富含GC的序列，这些序列可结合特异性蛋白1（Sp1）、Sp3和Sp4转录因子（TF）。本综述的重点是确定通过与NR相互作用而间接共同调节的Sp调节基因的一个重要子集。随后的研究表明，许多NR直接结合Sp1（或Sp3和Sp4），NR/Sp复合物结合富含GC的位点来调节基因表达，并且NR作为配体调节的核辅因子。此外，一些报告表明，NR反应性基因含有既结合Sp TF又结合NR的顺式元件，任一顺式元件的突变都会导致NR反应性（诱导性和/或基础性）丧失。这些基因的调节涉及DNA结合的Sp TF与近端或远端DNA结合的NR之间的相互作用，在某些情况下，基因表达还需要其他核辅因子。因此，许多NR反应性基因受NR/Sp复合物调节，这些基因可以被靶向NR的配体以及诱导Sp1、Sp3和Sp4降解的药物所靶向。
