Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.<b>Significance:</b> The gene regulation mechanisms that drive medulloblastoma are not well understood.
In 15 cases, we also examined expression of OTX2, a transcription factor recently indicated as a positive marker of medulloblastomas originating from cerebellar granule precursors.
The purpose of this study was to determine the incidence of c-Myc protein expression in medulloblastoma/primitive neuroectodermal tumor (MB/PNET) and to identify mechanisms in addition to c-myc gene amplification that lead to increased protein expression.
Recently, we showed that HIC1 is a direct transcriptional repressor of ATOH1, a proneural transcription factor required for normal cerebellar development, as well as for medulloblastoma cell viability.
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.
Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status.
GLI1 transcript was expressed in medulloblastomas with ATOH1 transcript, whereas high levels of MYC transcript were unrelated to NEUROG1 or ATOH1 expression.
We found that the transcription factor NEUROG1 (but not ATOH1) is expressed in cLPN, unlike normal adult cerebellum, and that fatty acid binding protein 4 (FABP4), typically found in adipocytes, is significantly overexpressed compared with both normal adult cerebellum and human MB.
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.
Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.
The mitogen-activated protein kinase (MAPK) pathway, but not the phosphoinositide 3-kinase (PI3K)-Akt pathway, was downregulated in medulloblastoma cells, whereas the PI3K-Akt pathway, but not the MAPK pathway, was downregulated in glioblastoma cells.
In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression.
OTX2, an oncogenic miR-206 target, overexpressed in all non-SHH medulloblastomas, is known to inhibit myogenic differentiation of medulloblastoma cells.