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

Author

Listed:
  • Qi Fei

    (Novartis Institutes for BioMedical Research)

  • Ke Shang

    (Novartis Institutes for BioMedical Research)

  • Jianhua Zhang

    (Novartis Institutes for BioMedical Research)

  • Shannon Chuai

    (Novartis Institutes for BioMedical Research)

  • Desheng Kong

    (Novartis Institutes for BioMedical Research)

  • Tianlun Zhou

    (Novartis Institutes for BioMedical Research)

  • Shijun Fu

    (Novartis Institutes for BioMedical Research)

  • Ying Liang

    (Novartis Institutes for BioMedical Research)

  • Chong Li

    (Novartis Institutes for BioMedical Research)

  • Zhi Chen

    (Novartis Institutes for BioMedical Research)

  • Yuan Zhao

    (Novartis Institutes for BioMedical Research)

  • Zhengtian Yu

    (Novartis Institutes for BioMedical Research)

  • Zheng Huang

    (Novartis Institutes for BioMedical Research)

  • Min Hu

    (Novartis Institutes for BioMedical Research)

  • Haiyan Ying

    (Novartis Institutes for BioMedical Research)

  • Zhui Chen

    (Novartis Institutes for BioMedical Research)

  • Yun Zhang

    (Novartis Institutes for BioMedical Research)

  • Feng Xing

    (Novartis Institutes for BioMedical Research)

  • Jidong Zhu

    (Novartis Institutes for BioMedical Research)

  • Haiyan Xu

    (Novartis Institutes for BioMedical Research)

  • Kehao Zhao

    (Novartis Institutes for BioMedical Research)

  • Chris Lu

    (Novartis Institutes for BioMedical Research)

  • Peter Atadja

    (Novartis Institutes for BioMedical Research)

  • Zhi-Xiong Xiao

    (College of Life Sciences, Sichuan University)

  • En Li

    (Novartis Institutes for BioMedical Research)

  • Jianyong Shou

    (Novartis Institutes for BioMedical Research
    Present address: Lilly China R&D Center, Shanghai 201203, China)

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.

Suggested Citation

  • Qi Fei & Ke Shang & Jianhua Zhang & Shannon Chuai & Desheng Kong & Tianlun Zhou & Shijun Fu & Ying Liang & Chong Li & Zhi Chen & Yuan Zhao & Zhengtian Yu & Zheng Huang & Min Hu & Haiyan Ying & Zhui Ch, 2015. "Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9651
    DOI: 10.1038/ncomms9651
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    Cited by:

    1. Bo Yu & Jun Su & Qiqi Shi & Qing Liu & Jun Ma & Guoqing Ru & Lei Zhang & Jian Zhang & Xichun Hu & Jianming Tang, 2022. "KMT5A-methylated SNIP1 promotes triple-negative breast cancer metastasis by activating YAP signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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