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HDAC6 promotes growth, migration/invasion, and self-renewal of rhabdomyosarcoma

Oncogene volume 40, pages 578–591 (2021)Cite this article

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Abstract

Rhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. The survival outcomes remain poor for patients with relapsed or metastatic disease. Effective targeted therapy is lacking due to our limited knowledge of the underlying cellular and molecular mechanisms leading to disease progression. In this study, we used functional assays in vitro and in vivo (zebrafish and xenograft mouse models) to demonstrate the crucial role of HDAC6, a cytoplasmic histone deacetylase, in driving RMS tumor growth, self-renewal, and migration/invasion. Treatment with HDAC6-selective inhibitors recapitulates the HDAC6 loss-of-function phenotypes. HDAC6 regulates cytoskeletal dynamics to promote tumor cell migration and invasion. RAC1, a Rho family GTPase, is an essential mediator of HDAC6 function, and is necessary and sufficient for RMS cell migration and invasion. High expression of RAC1 correlates with poor clinical prognosis in RMS patients. Targeting the HDAC6-RAC1 axis represents a promising therapeutic option for improving survival outcomes of RMS patients.

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Fig. 1: HDAC6 expression in RMS and conserved function of HDAC6 in regulating RMS tumor growth.
Fig. 2: HDAC6 regulates RMS growth by modulating cell cycle progression and tumor cell differentiation.
Fig. 3: HDAC6 regulates RMS tumor cell migration and self-renewal.
Fig. 4: HDAC6 regulates cytoskeletal dynamics to affect RMS cell migration.
Fig. 5: RAC1V12 promotes ERMS tumor growth and invasion.
Fig. 6: Tubastatin A treatment of RMS cells mimics the HDAC6 loss-of-function phenotypes.

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Acknowledgements

The authors want to thank Terra Vleeshouwer-Neumann and Amy Chen for technical assistance with some experiments. EYC is supported by NIH R01 CA196882. Lin Xu is supported by Children’s Cancer Fund and Rally Foundation.

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  1. These authors contributed equally: Thao Q. Pham, Kristin Robinson

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Thao Q. Pham, Kristin Robinson, Maria N. Pavlova & Eleanor Y. Chen

  2. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Lin Xu & Stephen X. Skapek

  3. Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Lin Xu

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  1. Thao Q. Pham
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EYC contributes to designing and performing the experiments, data analysis, and writing the paper. TP, KR, and MP contribute to performing the experiments and data analysis. LX and SS contribute to data analysis.

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Correspondence to Eleanor Y. Chen.

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Pham, T.Q., Robinson, K., Xu, L. et al. HDAC6 promotes growth, migration/invasion, and self-renewal of rhabdomyosarcoma. Oncogene 40, 578–591 (2021). https://doi.org/10.1038/s41388-020-01550-2

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