ASC deficiency suppresses proliferation and prevents medulloblastoma incidence.
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.
1] Neurobiology Curriculum, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [2] Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
E R W
ER
Knight
Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
E Y
EY
Patel
Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
C A
CA
Flowers
1] Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
A J
AJ
Crowther
1] Neurobiology Curriculum, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [3] Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
J P
JP
Ting
1] Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [3] Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [4] Department of Neurology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
C R
CR
Miller
1] Neurobiology Curriculum, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [2] Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [3] Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [4] Department of Neurology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
T R
TR
Gershon
1] Neurobiology Curriculum, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [2] Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [3] Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA [4] Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
M
M
Deshmukh
D000293:Adolescent; D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics*; D053468:CARD Signaling Adaptor Proteins; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C402202:PYCARD protein, human; C498534:Pycard protein, mouse; D016212:Transforming Growth Factor beta