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ASC deficiency suppresses proliferation and prevents medulloblastoma incidence

Oncogene volume 34, pages 394–402 (2015)Cite this article

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Abstract

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC’s role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.

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Acknowledgements

We thank Drs Vishva Dixit (Genentech), James Olson (Fred Hutchinson Cancer Research Center), Eva Anton (UNC) for generously sharing ASC−/−, ND2:SmoA1 and hGFAP-cre mice, respectively. We appreciate the technical assistance provided by Vivian Xu, Michael Conlin and Meera Patel in the Deshmukh Lab; Janice Weaver, Lily Wai and Yongjuan Xia in the UNC Histopathology Core; Terese Camp and Ling Li in the UNC Genomics Core; Mark Vincent Olorvida, Stephanie Cohen and Bentley Midkiff in the UNC Translational Pathology Laboratory (TPL); and Joel Parker, George Wu, Chandri Yandava and Chris Fan at UNC for bioinformatics and biostatistics guidance. The UNC TPL is supported in part by grants from the National Cancer Institute (3P30CA016086) and the UNC University Cancer Research Fund. We would like to thank members of the Deshmukh Laboratory for critical review of this manuscript. TRG is supported by NIH Grant 1K08NS077978 and St Baldrick’s Foundation. This work was supported by Grants NS042197 and GM078366 to MD.

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Authors and Affiliations

  1. Neurobiology Curriculum, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    E R W Knight, J P Ting, T R Gershon & M Deshmukh

  2. Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    E R W Knight, E Y Patel, C A Flowers, A J Crowther, C R Miller, T R Gershon & M Deshmukh

  3. Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    A J Crowther, J P Ting, C R Miller, T R Gershon & M Deshmukh

  4. Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    J P Ting

  5. Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    C R Miller

  6. Department of Neurology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    C R Miller & T R Gershon

  7. Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    M Deshmukh

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Knight, E., Patel, E., Flowers, C. et al. ASC deficiency suppresses proliferation and prevents medulloblastoma incidence. Oncogene 34, 394–402 (2015). https://doi.org/10.1038/onc.2013.577

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