1. Cancer Biology
  2. Cell Biology

Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling

  1. Yingqi Liu
  2. Lingling Li
  3. Xiaoqing Liu
  4. Yibo Wang
  5. Lingxia Liu
  6. Lu Peng
  7. Jiayuan Liu
  8. Lian zhang
  9. Guannan Wang
  10. Hongyuan Li
  11. Dongxu Liu
  12. Baiqu Huang
  13. Jun Lu  Is a corresponding author
  14. Yu Zhang  Is a corresponding author
  1. Northeast Normal University, China
  2. Chinese Academy of Sciences, China
  3. Auckland University of Technology, New Zealand
https://doi.org/10.7554/eLife.57617
Share this article
Cite this article
  1. Yingqi Liu
  2. Lingling Li
  3. Xiaoqing Liu
  4. Yibo Wang
  5. Lingxia Liu
  6. Lu Peng
  7. Jiayuan Liu
  8. Lian zhang
  9. Guannan Wang
  10. Hongyuan Li
  11. Dongxu Liu
  12. Baiqu Huang
  13. Jun Lu
  14. Yu Zhang
(2020)
Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling
eLife 9:e57617.
https://doi.org/10.7554/eLife.57617
  2. Download BibTeX
  3. Download .RIS

Abstract

Arginine methyltransferase PRMT7 is associated with human breast cancer metastasis. Endosomal FAK signalling is critical for cancer cell migration. Here we identified the pivotal roles of PRMT7 in promoting endosomal FAK signalling activation during breast cancer metastasis. PRMT7 exerted its functions through binding to scaffold protein SHANK2 and catalyzing di-methylation of SHANK2 at R240. SHANK2 R240 methylation exposed ANK domain by disrupting its SPN-ANK domain blockade, promoting in co-accumulation of dynamin2, talin, FAK, cortactin with SHANK2 on endosomes. In addition, SHANK2 R240 methylation activated endosomal FAK/cortactin signals in vitro and in vivo. Consistently, all the levels of PRMT7, methylated SHANK2, FAK Y397 phosphorylation and cortactin Y421 phosphorylation were correlated with aggressive clinical breast cancer tissues. These findings characterize the PRMT7-dependent SHANK2 methylation as a key player in mediating endosomal FAK signals activation, also point to the value of SHANK2 R240 methylation as a target for breast cancer metastasis.

Data availability

PDB accession number for SHANK2 structure analyse is pdb5G4X. Analysis of SHANK2 gene expression in human tissues using the Human Protein Atlas data.

The following previously published data sets were used

Article and author information

Author details

  1. Yingqi Liu

    The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Northeast Normal University, Changhcun, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3934-0673

  2. Lingling Li

    The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Xiaoqing Liu

    The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Northeast Normal University, Changhcun, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Yibo Wang

    Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Lingxia Liu

    The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Lu Peng

    The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Jiayuan Liu

    The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Lian zhang

    The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Northeast Normal University, Changhcun, China
    Competing interests
    The authors declare that no competing interests exist.

  9. Guannan Wang

    The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Northeast Normal University, Changhcun, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Hongyuan Li

    Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
    Competing interests
    The authors declare that no competing interests exist.

  11. Dongxu Liu

    School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand
    Competing interests
    The authors declare that no competing interests exist.

  12. Baiqu Huang

    The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Northeast Normal University, Changhcun, China
    Competing interests
    The authors declare that no competing interests exist.

  13. Jun Lu

    The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China
    For correspondence
    luj809@nenu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  14. Yu Zhang

    The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Northeast Normal University, Changhcun, China
    For correspondence
    zhangy288@nenu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3702-6541

Funding

National Natural Science Foundation of China (31870765)

  • Baiqu Huang

National Natural Science Foundation of China (31571317)

  • Jun Lu

National Natural Science Foundation of China (31570718)

  • Baiqu Huang

National Natural Science Foundation of China (31771335)

  • Yu Zhang

National Natural Science Foundation of China (31770825)

  • Jun Lu

National Natural Science Foundation of China (21807098)

  • Yibo Wang

Natural Science Foundation of Jilin Province (20180101232JC)

  • Jun Lu

Natural Science Foundation of Jilin Province (20180101234JC)

  • Yu Zhang

Natural Science Foundation of Jilin Province (20200404106YY)

  • Yu Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal works were conducted in accordance with the IACUC guidelines and with the protocol approved by the IACUC at the Northeast Normal University, reference assurance number AP2013011.

Human subjects: Human breast tumour specimens were obtained from the Second Hospital of Jilin University, China. All the breast cancer tissue samples were collected from 27 patients enrolled on pathology department of the Second Hospital of Jilin University. All the samples were diagnosed by the pathology department of the Second Hospital of Jilin University to determine the stage and subtype of the breast tumour. This experiment is an immunohistochemical study, no informed consent was needed due to the use of post-diagnostic left-over material. Ethical approval was obtained from the Ethics Review Committee of the Second Hospital of Jilin University (2019-107).

Copyright

© 2020, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,382
    views
  • 435
    downloads
  • 17
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yingqi Liu
  2. Lingling Li
  3. Xiaoqing Liu
  4. Yibo Wang
  5. Lingxia Liu
  6. Lu Peng
  7. Jiayuan Liu
  8. Lian zhang
  9. Guannan Wang
  10. Hongyuan Li
  11. Dongxu Liu
  12. Baiqu Huang
  13. Jun Lu
  14. Yu Zhang
(2020)
Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling
eLife 9:e57617.
https://doi.org/10.7554/eLife.57617

Share this article

https://doi.org/10.7554/eLife.57617

Categories and tags

Research organism

Further reading

    1. Cancer Biology

    Non-destructive in situ monitoring of structural changes of 3D tumor spheroids during the formation, migration, and fusion process

    Ke Ning, Yuanyuan Xie ... Ling Yu
    Research Article

    For traditional laboratory microscopy observation, the multi-dimensional, real-time, in situ observation of three-dimensional (3D) tumor spheroids has always been the pain point in cell spheroid observation. In this study, we designed a side-view observation petri dish/device that reflects light, enabling in situ observation of the 3D morphology of cell spheroids using conventional inverted laboratory microscopes. We used a 3D-printed handle and frame to support a first-surface mirror, positioning the device within a cell culture petri dish to image cell spheroid samples. The imaging conditions, such as the distance between the mirror and the 3D spheroids, the light source, and the impact of the culture medium, were systematically studied to validate the in situ side-view observation. The results proved that placing the surface mirror adjacent to the spheroids enables non-destructive in situ real-time tracking of tumor spheroid formation, migration, and fusion dynamics. The correlation between spheroid thickness and dark core appearance under light microscopy and the therapeutic effects of chemotherapy doxorubicin and natural killer cells on spheroids’ 3D structure was investigated.

    1. Cancer Biology

    NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

    Ismail M Meraz, Mourad Majidi ... Jack A Roth
    Research Article

    Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11mt/aPD1R tumors but was synergistic in KRASwt/aPD1S H1299. NPRL2 also showed a significant antitumor effect on KRASmt/aPD1R LLC2 syngeneic-tumors. The antitumor effect was correlated with increased infiltration of human cytotoxic-T, HLA-DR+DC, CD11c+DC, and downregulation of myeloid and regulatory-T cells in TME. Antitumor effect was abolished upon in-vivo depletion of CD8-T, macrophages, and CD4-T cells whereas remained unaffected upon NK-cell depletion. A distinctive protein-expression profile was found after NPRL2 treatment. IFNγ, CD8b, and TBX21 associated with T-cell functions were significantly increased, whereas FOXP3, TGFB1/B2, and IL-10RA were strongly inhibited by NPRL2. A list of T-cell co-inhibitory molecules was also downregulated. Restoration of NPRL2 exhibited significantly slower tumor growth in humanized-mice, which was associated with increased presence of human cytotoxic-T, and DC and decreased percentage of Treg, MDSC, and TAM in TME. NPRL2-stable cells showed a substantial increase in colony-formation inhibition and heightened sensitivity to carboplatin. Stable-expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR signaling. Taken-together, NPRL2 gene-therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen-presentation and cytotoxic immune-cell activation.