Lastly, we show the distribution of AZD1152-HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells.
Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.
Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients.
We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest.
Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.
Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066.
JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling.
Here, we review the relationship of MYC family proteins to the four molecularly distinct medulloblastoma subgroups, discuss the possible roles MYC plays in each of these subgroups and in the developing cells of the posterior fossa, and speculate on possible therapeutic strategies targeting MYC.
The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others.
Antisense-based knockdown of miR-512-5p (mature sequence of miR-512-2) resulted in significant upregulation of MYCC expression in HeLa and A549 cells, while forced overexpression of miR-512-2 in medulloblastoma/PNET cell lines DAOY, UW-228-2, PFSK resulted in the downregulation of MYCC protein.
To understand the contribution of miR-183~96~182 to the pathogenesis of this aggressive subtype of medulloblastoma, we analyzed global gene expression and proteomic changes that occur upon modulation of miRNAs in this cluster individually and as a group in MYC-amplified medulloblastoma cells.
This mouse model should significantly accelerate understanding and treatment of the most aggressive form of medulloblastoma and infers distinct roles for MYC and MYCN in tumorigenesis.
The association of clinically aggressive medulloblastoma with MYC expression, large cell/anaplastic change and high levels of photoreceptor differentiation transcripts has also been noted in several studies.
It is known that overexpression and/or amplification of the MYC oncogene is associated with poor clinical outcome, but the molecular mechanisms and the MYC downstream effectors in MB remain still elusive.
Additional analysis by interphase fluorescence in situ hybridisation (iFISH), PCR-based mapping and SNP-array revealed this novel amplification at 8q24.22-q24.23 is independent of MYC amplification at 8q24.21, and is unique to medulloblastoma in over 800 cancer cell lines assessed from different tumour types, suggesting it contains key genes specifically involved in medulloblastoma development.
Since FISH could easily detect most cases in the moderate-to-high myc gene amplification (> 5-fold CN) group, the FISH assay has utility in detecting subsets of MB with poorer prognosis.