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LIMK2 promotes melanoma tumor growth and metastasis through G3BP1-ESM1 pathway-mediated apoptosis inhibition

Oncogene volume 42, pages 1478–1491 (2023)Cite this article

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Abstract

Melanoma is the leading cause of skin cancer-related deaths, and current melanoma therapies, including targeted therapies and immunotherapies, benefit only a subset of metastatic melanoma patients due to either intrinsic or acquired resistance. LIM domain kinase 2 (LIMK2) is a serine/threonine kinase that plays an important role in the regulation of actin filament dynamics. Here, we show that LIMK2 is overexpressed in melanoma, and its genetic or pharmacological inhibition impairs melanoma tumor growth and metastasis in both cell culture and mice. To determine the mechanism by which LIMK2 promotes melanoma tumor growth and metastatic progression, we performed a phosphoproteomics analysis and identified G3BP1 as a key LIMK2 target, which mirrored the effects of LIMK2 inhibition when inhibited. To further determine the role of G3BP1 downstream of LIMK2, we knocked down the expression of G3BP1, performed RNA-seq analysis, and identified ESM1 as a downstream target of G3BP1. G3BP1 was required for ESM1 mRNA stability, and ESM1 ectopic expression rescued LIMK2 or G3BP1 inhibition-induced suppression of melanoma growth and metastatic attributes. These results collectively identify the LIMK2→G3BP1→ESM1 pathway as a facilitator of melanoma tumor growth and metastasis and document that LIMK2 is a therapeutically tractable target for melanoma therapy.

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Fig. 1: LIMK2 is overexpressed in melanoma cells and its pharmacological inhibition impairs melanoma growth and metastatic attributes.
Fig. 2: Pharmacological inhibition of LIMK2 inhibits melanoma tumor growth and metastasis in naïve and drug-resistant melanoma in vivo.
Fig. 3: TMT10-based global phosphoproteomics analysis identifies key pathways and targets of LIMK2.
Fig. 4: G3BP1 is overexpressed in melanoma and its loss inhibits melanoma growth and metastatic attributes.
Fig. 5: ESM1 is a G3BP1 target, and its mRNA level is regulated by G3BP1 via stabilization.
Fig. 6: ESM1 mediates downstream effects of G3BP1 and LIMK2.
Fig. 7: The LIMK2→G3BP1→ESM1 pathway promotes melanoma growth and metastasis by suppressing apoptosis.
Fig. 8: Proteolysis targeting chimera (PROTAC)-based inhibition of LIMK2 suppresses melanoma tumor growth and metastasis in naïve and drug-resistant melanoma cells in vivo.

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All data and relevant information are available in the main text or the supplementary materials. Materials request should be addressed to nwajapey@uab.edu

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Parmanand Malvi, Dhana Sekhar Reddy, Raj Kumar, Suresh Chava, Keshab Parajuli & Narendra Wajapeyee

  2. Department of Pathology, Yale University School of Medicine, New Haven, CT, 06511, USA

    Sneha Burela & Xuchen Zhang

  3. UAB O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Narendra Wajapeyee

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Contributions

PM, DR, RK, SC, and NW designed the experiments. PM, DR, RK, SC, SB, and KP performed the experiments. PM, DR, RJ, SC, SB, KP, XZ, and NW analyzed the data. PM, DR, RK, SC, and NW wrote the manuscript. All the authors read and approved the final version of the manuscript.

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Correspondence to Narendra Wajapeyee.

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Malvi, P., Reddy, D.S., Kumar, R. et al. LIMK2 promotes melanoma tumor growth and metastasis through G3BP1-ESM1 pathway-mediated apoptosis inhibition. Oncogene 42, 1478–1491 (2023). https://doi.org/10.1038/s41388-023-02658-x

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