Small molecule Z363 co-regulates TAF10 and MYC via the E3 ligase TRIP12 to suppress tumour growth.
Small molecule Z363 co-regulates TAF10 and MYC via the E3 ligase TRIP12 to suppress tumour growth.
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DOI：
10.1002/ctm2.1153
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发表时间：
2023-01
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
MYC癌蛋白，也称为基因的主调节因子，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等。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。CRISPR/Cas9方法用于产生KO细胞模型。采用Western blot分析癌细胞（MCF 7、A549、HepG 2细胞）中MYC和TATA结合蛋白相关因子10（TAF 10）的表达。进行细胞培养研究以确定小分子（Z363119456、Z363）影响MYC和TAF 10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。Z363激活甲状腺激素受体相互作用蛋白12（TRIP 12），其在Thr 58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，TRIP 12还诱导TAF 10降解，从而降低MYC蛋白水平。TRIP 12是一种E3连接酶，通过抑制MYC或TAF 10活性直接和间接控制MYC水平。总之，这些结果证明了Z363的抗癌特性，Z363是一种由TAF 10和MYC共同调节的小分子。Z363通过共调节TAF 10和MYC对癌细胞和异种移植模型发挥抗癌作用。TRIP 12通过直接和间接抑制MYC活性在Z363诱导的癌细胞凋亡中起重要作用。Z363通过激活其磷酸化促进MYC泛素化。Z363诱导TAF 10降解，从而降低MYC蛋白水平。
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. Z363 exerts an anti‐cancer effect on cancer cell and xenograft models by co‐regulating TAF10 and MYC. TRIP12 plays an important role in Z363‐induced cancer cell apoptosis by directly and indirectly inhibiting MYC activity. Z363 promotes MYC ubiquitination by activating its phosphorylation. Z363 induces TAF10 degradation, which reduces MYC protein levels.
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DOI：
10.1016/j.bbagrm.2014.03.005
发表时间：
2015-05
影响因子：
4.7
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.0900121106
发表时间：
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影响因子：
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影响因子：
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