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AKT-mediated regulation of chromatin ubiquitylation and tumorigenesis through Mel18 phosphorylation

Oncogene volume 40, pages 2422–2436 (2021)Cite this article

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Abstract

Polycomb repressor complex 1 (PRC1) is linked to the regulation of gene expression and histone ubiquitylation conformation, which contributes to carcinogenesis. However, the upstream regulators of PRC1 biogenesis machinery remain obscure. Here, we report that the polycomb group-related mammalian gene Mel18 is a target of the protein kinase AKT. AKT phosphorylates Mel18 at T334 to disrupt the interaction between Mel18 and other PRC1 members, leading to attenuated PRC1-dependent ubiquitylation of histone H2A at Lys119. As such, PRC1 target genes, many of which are known oncogenes, are derepressed upon T334-Mel18 phosphorylation, which promotes malignant behaviours, including cell proliferation, tumour formation, migration and invasion, bone and brain metastatic lesion formation. Notably, a positive correlation between AKT activity and pT334-Mel18 is observed, and prognostic models based on p-AKT and pT334-Mel18 that predicted overall survival and distant metastasis-free survival in breast cancer patients are established. These findings have implications for understanding the role of AKT and its associated proteins in chromatin ubiquitylation, and also indicate the AKT-Mel18-H2AK119ub axis as a novel prognostic biomarker and therapeutic target for cancer patients.

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Fig. 1: AKT negatively regulates ubiquitylation of histone H2A at Lys119.
Fig. 2: Mel18 interacts with AKT.
Fig. 3: Identification of Mel18 as a downstream phosphorylation substrate of AKT.
Fig. 4: AKT-mediated phosphorylation of Mel18 at T334 promotes breast cancer cells progression.
Fig. 5: Phosphorylation of Mel18 at T334 by AKT1 disrupts PRC1 complex and suppresses H2AK119 ubiquitylation.
Fig. 6: P-Mel18 is correlated with p-AKT in clinical breast cancer samples.
Fig. 7: Proposed model of phosphorylation of Mel18 by AKT suppresses H2AK119ub and promotes oncogenic function.

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Data availability

The correlation between the protein levels of AKT1 and Pcgf paralogues was performed by using the publicly available mass spectrometry-based proteomics data from cBioPortal (http://www.cbioportal.org/, TCGA Firehose legacy). All the ChIP-seq databases generated in this paper have been deposited in the Genome Sequence Archive (GSA, https://bigd.big.ac.cn/gsa/) under the accession number CRA002474, CRA003431 and CRA003414.

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Acknowledgements

We thank Prof. Wei-Guo Zhu (Shenzhen University) for providing Flag-H2A, Flag-H2B, Flag-H3 and Flag-H4 plasmids.

Funding

This study was supported by the Natural Science Foundation of China (81772624, 81572605, 81772835, 81972481, 81630079, and 81972855), the Science and Technology Project of Guangzhou (201803010007), China Postdoctoral Science Foundation (2020M683107) and the Natural Science Foundation of Guangdong Province (2019A1515011209).

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  1. These authors contributed equally: Jia Mai, Xiao-Dan Peng, Jun Tang

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

    Jia Mai, Xiao-Dan Peng, Jun Tang, Tian Du, Yu-Hong Chen, Zi-Feng Wang, Hai-Liang Zhang, Jun-Hao Huang, Zhuo-Yan Zhong, Dong Yang, Zhi-Ling Li, Yun Huang, Gong-Kan Feng, Xiao-Feng Zhu & Rong Deng

  2. Department of Laboratory Medicine, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China

    Jia Mai

  3. Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Jun Tang, Tian Du & Jun-Hao Huang

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Mai, J., Peng, XD., Tang, J. et al. AKT-mediated regulation of chromatin ubiquitylation and tumorigenesis through Mel18 phosphorylation. Oncogene 40, 2422–2436 (2021). https://doi.org/10.1038/s41388-020-01602-7

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