背景:MYC癌蛋白,也被称为基因的主要调节因子,是调节许多生理过程的转录因子,包括细胞周期控制,凋亡,蛋白质合成和细胞粘附,在其他人中。MYC在大约70%的人类癌症中过表达。鉴于其在癌症生物学中的普遍作用,MYC下调已成为一种有吸引力的癌症治疗策略。
方法:使用CRISPR/Cas9方法产生KO细胞模型。蛋白质印迹用于分析MYC和TATA结合蛋白相关因子10(TAF10)在癌细胞(MCF7、A549、HepG2细胞)中的表达进行细胞培养研究以确定小分子(Z363119456、Z363)影响MYC和TAF10表达和功能的机制。进行小鼠研究以研究Z363调节对肿瘤生长的影响。
结果:Z363激活甲状腺激素受体相互作用蛋白12(TRIP12),它在Thr58磷酸化MYC,导致MYC泛素化和降解,从而调节MYC靶基因。重要的是,TRIP12还诱导TAF10降解,降低MYC蛋白水平。TRIP12,一种E3连接酶,通过抑制MYC或TAF10活性直接和间接控制MYC水平。
结论:总之,这些结果证明了Z363的抗癌特性,Z363是一种由TAF10和MYC共同调节的小分子。
The MYC oncoprotein, also known as the master regulator of genes, is a transcription factor that regulates numerous physiological processes, including cell cycle control, apoptosis, protein synthesis and cell adhesion, among others. MYC is overexpressed in approximately 70% of human cancers. Given its pervasive role in cancer biology, MYC down-regulation has become an attractive cancer treatment strategy.
The CRISPR/Cas9 method was used to produce KO cell models. Western blot was used to analyzed the expressions of MYC and TATA-binding proteinassociated factors 10 (
TAF10) in cancer cells (MCF7, A549, HepG2 cells) Cell culture studies were performed to determine the mechanisms by which small molecules (Z363119456, Z363) affects MYC and
TAF10 expressions and functions. Mouse studies were carried out to investigate the impact of Z363 regulation on tumor growth.
Z363 activate Thyroid hormone Receptor-interacting Protein 12 (TRIP12), which phosphorylates MYC at Thr58, resulting in MYC ubiquitination and degradation and thereby regulating MYC target genes. Importantly, TRIP12 also induces
TAF10 degradation, which reduces MYC protein levels. TRIP12, an E3 ligase, controls MYC levels both directly and indirectly by inhibiting MYC or
TAF10 activity.
In summary,these results demonstrate the anti-cancer properties of Z363, a small molecule that is co-regulated by
TAF10 and MYC.