MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, China.
The Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, Davis, California.
Mol Cancer Res. 2018 Nov;16(11):1641-1651. doi: 10.1158/1541-7786.MCR-18-0070. Epub 2018 Jul 12.
Differentiated embryonic chondrocyte expressed gene 1 (DEC1, also known as Sharp2/Stra13/BHLHE40) is a basic helix-loop-helix transcription factor that plays an important role in circadian rhythms, cell proliferation, apoptosis, cellular senescence, hypoxia response, and epithelial-to-mesenchymal transition of tumor cells. Secretory clusterin (sCLU) is a cytoprotective protein that guards against genotoxic stresses. Here, clusterin (CLU) was identified as a novel target gene of DEC1 and suppresses DNA damage-induced cell death in tumor cells. Mechanistically, based on chromatin immunoprecipitation and luciferase assays, DEC1 binds to and activates the promoter of the CLU gene. DEC1 and DNA-damaging agents induce sCLU expression, whereas DEC1 knockdown decreases the expression of sCLU upon DNA damage. Moreover, the data demonstrate that DEC1 inhibits, whereas sCLU knockdown enhances, DNA damage-induced cell death in MCF7 breast cancer cells. Given that DEC1 and sCLU are frequently overexpressed in breast cancers, these data provide mechanistic insight into DEC1 as a prosurvival factor by upregulating sCLU to reduce the DNA damage-induced apoptotic response. Together, this study reveals sCLU as a novel target of DEC1 which modulates the sensitivity of the DNA damage response. DEC1 and sCLU are frequently overexpressed in breast cancer, and targeting the sCLU-mediated cytoprotective signaling pathway may be a novel therapeutic approach. .
分化胚胎软骨细胞表达基因 1（DEC1，也称为 Sharp2/Stra13/BHLHE40）是一种基本螺旋-环-螺旋转录因子，在昼夜节律、细胞增殖、细胞凋亡、细胞衰老、缺氧反应和肿瘤细胞上皮-间充质转化中发挥重要作用。分泌型载脂蛋白 J（sCLU）是一种细胞保护蛋白，可防止遗传毒性应激。在这里，载脂蛋白 J（CLU）被鉴定为 DEC1 的一个新靶基因，并抑制肿瘤细胞中 DNA 损伤诱导的细胞死亡。在机制上，基于染色质免疫沉淀和荧光素酶测定，DEC1 结合并激活 CLU 基因的启动子。DEC1 和 DNA 损伤剂诱导 sCLU 表达，而 DEC1 敲低则降低 DNA 损伤时 sCLU 的表达。此外，数据表明 DEC1 抑制而 sCLU 敲低增强 MCF7 乳腺癌细胞中 DNA 损伤诱导的细胞死亡。鉴于 DEC1 和 sCLU 在乳腺癌中经常过度表达，这些数据为 DEC1 作为一种生存促进因子提供了机制上的见解，通过上调 sCLU 来减少 DNA 损伤诱导的凋亡反应。总之，这项研究揭示了 sCLU 作为 DEC1 的一个新靶标，调节 DNA 损伤反应的敏感性。DEC1 和 sCLU 在乳腺癌中经常过度表达，靶向 sCLU 介导的细胞保护信号通路可能是一种新的治疗方法。
