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ACTN4 regulates the stability of RIPK1 in melanoma

Oncogene volume 37, pages 4033–4045 (2018)Cite this article

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Abstract

The actin crosslinking protein α-actinin-4 (ACTN4) is emerging as an important contributor to the pathogenesis of cancer. This has largely been attributed to its role in regulating cytoskeleton organization and its involvement in transcriptional regulation of gene expression. Here we report a novel function of ACTN4 as a scaffold necessary for stabilization of receptor-interacting protein kinase 1 (RIPK1) that we have recently found to be an oncogenic driver in melanoma. ACTN4 bound to RIPK1 and cellular inhibitor of apoptosis protein 1 (cIAP1) with its actin-binding domain at the N-terminus and the CaM-like domain at the C-terminus, respectively. This facilitated the physical association between RIPK1 and cIAP1 and was critical for stabilization of RIPK1 that in turn activated NF-κB. Functional investigations showed that silencing of ACTN4 suppressed melanoma cell proliferation and retarded melanoma xenograft growth. In contrast, overexpression of ACTN4 promoted melanocyte and melanoma cell proliferation and moreover, prompted melanocyte anchorage-independent growth. Of note, the expression of ACTN4 was transcriptionally activated by NF-κB. Taken together, our findings identify ACTN4 as an oncogenic regulator through driving a feedforward signaling axis of ACTN4-RIPK1-NF-κB, with potential implications for targeting ACTN4 in the treatment of melanoma.

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Acknowledgements

This work was supported by the National Health and Medical Research Council (NHMRC) (APP1083496 and APP1099947) and the Natural Science Foundation of China (NSFC) (81772908). L.J. and C.C.J. are recipients of Cancer Institute NSW Fellowships.

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Authors and Affiliations

  1. School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, 2308, Australia

    Yuan Yuan Zhang, Xiao Ying Liu, Chen Chen Jiang & Lei Jin

  2. School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, 2308, Australia

    Hessam Tabataba, Jia Yu Wang, Xu Guang Yan, Margaret Farrelly, Su Tang Guo & Xu Dong Zhang

  3. School of Life Science, Anhui Medical University, Hefei, Anhui, 230000, China

    Xiao Ying Liu

  4. Cancer Research Program, Hunter Medical Research Institute, New Lambton, NSW, 2305, Australia

    Chen Chen Jiang, Xu Dong Zhang & Lei Jin

  5. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, 030013, China

    Su Tang Guo

  6. Children’s Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, NSW, 2750, Australia

    Tao Liu

  7. Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA

    Hung-Ying Kao

  8. School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, 2308, Australia

    Rick F. Thorne

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Zhang, Y.Y., Tabataba, H., Liu, X.Y. et al. ACTN4 regulates the stability of RIPK1 in melanoma. Oncogene 37, 4033–4045 (2018). https://doi.org/10.1038/s41388-018-0260-x

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