ACTN4 regulates the stability of RIPK1 in melanoma

Yuan Yuan Zhang, Hessam Tabataba, Xiao Ying Liu, Jia Yu Wang, Xu Guang Yan, Margaret Farrelly, Chen Chen Jiang, Su Tang Guo, Tao Liu, Hung Ying Kao, Rick F. Thorne, Xu Dong Zhang, Lei Jin

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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.

Original languageEnglish
Pages (from-to)4033-4045
Number of pages13
JournalOncogene
Volume37
Issue number29
DOIs
Publication statusPublished - 2018 Jul 19

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zhang, Y. Y., Tabataba, H., Liu, X. Y., Wang, J. Y., Yan, X. G., Farrelly, M., Jiang, C. C., Guo, S. T., Liu, T., Kao, H. Y., Thorne, R. F., Zhang, X. D., & Jin, L. (2018). ACTN4 regulates the stability of RIPK1 in melanoma. Oncogene, 37(29), 4033-4045. https://doi.org/10.1038/s41388-018-0260-x