Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53.

Qi Fei,Ying Liang,Yun Zhang,Kehao Zhao,Desheng Kong,Peter Atadja,Zheng Huang,Zhi Chen,Zhengtian Yu,Jidong Zhu,Shijun Fu,Chong Li,Haiyan Ying,Ke Shang,Feng Xing,Haiyan Xu,Tianlun Zhou,Zhui Chen,Jianhua Zhang,Jianyong Shou,Yuan Zhao,Shannon Chuai,En Li,Min Hu,Zhi‐Xiong Jim Xiao ,Chris X Lu

doi:10.1038/ncomms9651

Qi Fei, Ying Liang + Show 24 more

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https://doi.org/10.1038/ncomms9651

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Abstract

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.

Highlights

SETDB1 is a histone H3K9 methyltransferase that has a critical role in early development
In an Hepatitis C Virus (HCV)-induced hepatocellular carcinoma (HCC) study (GSE6764), gene expression was measured at various stages of tumorigenesis
We found that the expression of SETDB1 correlated well with the grade of tumorigenesis with later-stage cancer expressing higher level of SETDB1 (Fig. 1a)

Summary

Introduction

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. 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. SETDB1 attenuation reduces the p53K370me[2] 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. HCC is a heterogeneous disease driven by progressive genetic aberrations including silencing of tumour suppressor genes, oncogene activation and chromosomal anomalies. GOF TP53 mutations contribute to genomic instability, inactivation of P63 and P73, aberrant gene transcription, anti-apoptosis activity and enhanced tumour cell invasion and migration. SETDB1 executes its role on cancer cell growth through di-methylating p53 at K370

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