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Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB

Oncogene volume 37, pages 847–860 (2018)Cite this article

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Abstract

Cellular movement is controlled by small GTPases, such as RhoA. Although migration is crucial for cancer cell invasion, the specific role of RhoA in tumor formation is unclear. Inducing skin tumors in mice with a keratinocyte-restricted loss of RhoA, we observed increased tumor frequency, growth and invasion. In vitro invasion assays revealed that in the absence of RhoA cell invasiveness is increased in a Rho-associated protein kinase (ROCK) activation and cell contraction-dependent manner. Surprisingly, loss of RhoA causes increased Rho signaling via overcompensation by RhoB because of reduced lysosomal degradation of RhoB in Gamma-aminobutyric acid receptor-associated protein (GABARAP)+ autophagosomes and endosomes. In the absence of RhoA, RhoB relocalized to the plasma membrane and functionally replaced RhoA with respect to invasion, clonogenic growth and survival. Our data demonstrate for the first time that RhoA is a tumor suppressor in 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate skin carcinogenesis and identify Rho signaling dependent on RhoA and RhoB as a potent driver of tumor progression.

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Acknowledgements

We thank Volkan Turan and Anna Fossum for expert technical help. We thank Dr Anders H Lund and Dr Klemens Rottner for kindly providing antibodies and plasmids, and Dr Kim Bak Jensen for critical reading of the manuscript and advice. The ultrastructural work was carried out in the Centre of Microscopy and Imaging affiliated to Anatomy at NUI Galway.

Author contributions

AG-M planned and performed experiments, analyzed data and wrote the manuscript. HL, EP, KP, AS and FQ performed experiments and analyzed data. KR provided crucial advice and tools. CB planned experiments, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. Biotech Research and Innovation Centre, BRIC, University of Copenhagen, Copenhagen, Denmark

    A García-Mariscal, H Li, E Pedersen, K Peyrollier & C Brakebusch

  2. Beatson Institute, Glasgow, UK

    K M Ryan

  3. Skin and Extracellular Matrix Research Group, Anatomy, NUI, Galway, Ireland

    A Stanley & F Quondamatteo

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  1. A García-Mariscal
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Correspondence to C Brakebusch.

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García-Mariscal, A., Li, H., Pedersen, E. et al. Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB. Oncogene 37, 847–860 (2018). https://doi.org/10.1038/onc.2017.333

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