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Palmitoylacyltransferase Zdhhc9 inactivation mitigates leukemogenic potential of oncogenic Nras

Leukemia volume 30, pages 1225–1228 (2016)Cite this article

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Hyperactivation of rat sarcoma (RAS) is common in human cancer.1 As RAS proteins are difficult to target, identification of alternative means to block RAS oncogenic signaling is critical for developing cancer therapies.2 We have previously shown that palmitoylation of neuroblastoma RAS (NRAS), which is predominantly mutated in human hematological malignances,3 is essential for its leukemogenic activity, suggesting that targeting RAS palmitoylation may be an effective therapy at least for NRAS-related cancers.4 S-palmitoylation is catalyzed by palmitoylacyltransferases (PATs).5 To date, at least 23 mammalian PATs have been identified, a protein motif containing aspartate-histidine-histidine-cysteine residues (DHHC) conserved motif embedded in a cysteine-rich domain.6 Zinc-finger DHHC-type containing 9 (ZDHHC9, a transmembrane protein) has been shown to function as a mammalian PAT with specificity for H- and NRAS in vitro.7 In this study, we investigated the role of Zdhhc9 in modification of Nras in vivo, as well as its roles in normal hematopoiesis and in the development of leukemias induced by oncogenic Nras.

To determine whether Zdhhc9 is a bona fide PAT for Ras palmitoylation in vivo, we performed the acyl-biotinyl exchange assay8 to assess the palmitoylation status of Ras in BM cells from Zdhhc9KO mice and the wild-type control mice. The results show that the palmitoylation level of Ras is significantly decreased, yet not abolished, in BM of Zdhhc9KO mice, comparing with their wild-type counterparts (Figure 1b). This result demonstrates that Zdhhc9 is a Ras PAT in vivo, but it is not the only one.

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Figure 1
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Acknowledgements

We thank Professor Maurine E. Linder (Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY, USA) for generous help and critical discussions of the project, and Professor Jing Zhang (McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA) for technical support. This work was supported by research funds from the National Natural Science Foundation of China (Grant 81230055 to RR, 81170506 to PL and 81300402 to BJ), the Shanghai Municipal Commission for Outstanding Academic Leader Program (Grant 12XD1403500 to RR) and the China Postdoctoral Science Foundation (Grant 2013M530201 to BJ).

Author contributions

PL participated in the design of the study, performed research, analyzed data, and drafted the manuscript; BJ performed experiments, analyzed data, and wrote the manuscript; RZ and CZ performed animal experiments; HZ and DL were responsible for cell culture and retrovirus production; MW helped to carry out acyl-biotinyl exchange palmitoylation detection assays; XZ and QQ assisted in performing flow cytometric analysis of HSCs; JL helped the design of the study and RR designed research, analyzed data, and wrote the paper.

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  1. P Liu and B Jiao: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    P Liu, B Jiao, R Zhang, H Zhao, C Zhang, M Wu, D Li, X Zhao, Q Qiu, J Li & R Ren

  2. Department of Biology, Brandeis University, Waltham, MA, USA

    R Ren

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  1. P Liu
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Liu, P., Jiao, B., Zhang, R. et al. Palmitoylacyltransferase Zdhhc9 inactivation mitigates leukemogenic potential of oncogenic Nras. Leukemia 30, 1225–1228 (2016). https://doi.org/10.1038/leu.2015.293

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