Fei Qi, Shang Ke, Zhang Jianhua, Chuai Shannon, Kong Desheng, Zhou Tianlun, Fu Shijun, Liang Ying, Li Chong, Chen Zhi, Zhao Yuan, Yu Zhengtian, Huang Zheng, Hu Min, Ying Haiyan, Chen Zhui, Zhang Yun, Xing Feng, Zhu Jidong, Xu Haiyan, Zhao Kehao, Lu Chris, Atadja Peter, Xiao Zhi-Xiong, Li En, Shou Jianyong
Novartis Institutes for BioMedical Research, Shanghai 201203, China.
College of Life Sciences, Sichuan University, Chengdu 610064, China.
Nat Commun. 2015 Oct 16;6:8651. doi: 10.1038/ncomms9651.
SETDB1 is a histone H3K9 methyltransferase that has a critical role in early development. It is located within a melanoma susceptibility locus and facilitates melanoma formation. However, the mechanism by which SETDB1 regulates tumorigenesis remains unknown. Here we report the molecular interplay between SETDB1 and the well-known hotspot gain-of-function (GOF) TP53 R249S mutation. We show that in hepatocellular carcinoma (HCC) SETDB1 is overexpressed with moderate copy number gain, and GOF TP53 mutations including R249S associate with this overexpression. Inactivation of SETDB1 in HCC cell lines bearing the R249S mutation suppresses cell growth. The TP53 mutation status renders cancer cells dependent on SETDB1. Moreover, SETDB1 forms a complex with p53 and catalyses p53K370 di-methylation. SETDB1 attenuation reduces the p53K370me2 level, which subsequently leads to increased recognition and degradation of p53 by MDM2. Together, we provide both genetic and biochemical evidence for a mechanism by which SETDB1 regulates cancer cell growth via methylation of p53.
SETDB1是一种组蛋白H3K9甲基转移酶，在早期发育中起关键作用。它位于一个黑色素瘤易感位点内，促进黑色素瘤的形成。然而，SETDB1调节肿瘤发生的机制尚不清楚。在这里，我们报告了SETDB1与著名的热点功能获得性（GOF）TP53 R249S突变之间的分子相互作用。我们发现，在肝细胞癌（HCC）中，SETDB1因中等拷贝数增加而过度表达，包括R249S在内的GOF TP53突变与这种过度表达相关。在携带R249S突变的HCC细胞系中使SETDB1失活可抑制细胞生长。TP53突变状态使癌细胞依赖于SETDB1。此外，SETDB1与p53形成复合物并催化p53K370二甲基化。SETDB1的减弱降低了p53K370me2水平，随后导致MDM2对p53的识别和降解增加。总之，我们提供了遗传和生化证据，证明SETDB1通过p53甲基化调节癌细胞生长的机制。
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