Ubiquitin ligases and medulloblastoma: genetic markers of the four consensus subgroups identified through transcriptome datasets

The ubiquitin proteasome system regulates key cellular processes in normal and in cancer cells. Herein, we review published data on the role of ubiquitin ligases in the four major subgroups of medulloblastoma (MB). While conventional literature serves as an initial source of information on cellular pathways in MB, large publicly available datasets of gene expression can be used to add information not previously identified in the literature. By analysing the publicly available Cavalli dataset, we show that increased expression of ZNRF3 characterizes the WNT subgroup of MB. The ZNRF3 gene codes for an E3 ligase associated with WNT receptors. Loss of a copy of chromosome 6 in a subtype of the WNT group was associated with decreased expression of the gene encoding the E3 ligase RNF146. While the E3 ligase SMURF regulates SHH receptors, increased expression of the gene encoding the Cullin Ring E3 adaptor PPP2R2C was statistically a better genetic marker of the SHH group. Genes whose expression was statistically strongly related to Group 3 included the E3 ligase gene TRIM58, and the gene for the E3 ligase adaptor, PPP2R2B. Group 4 MB was associated with expression of genes encoding several E3 ligases and E3 ligase adaptors involved in ribosome biogenesis. Increased expression of the genes encoding the E3 ligase adaptors and transcription repressors ZBTB18 and ZBTB38 were also noted in subgroup 4. These data suggest that several E3 ligases and their adaptors should be investigated as therapeutic targets for subgroup specific MB brain tumors.

Keywords: Medulloblastoma; Neddylation; Protein phosphatase 2A (PP2A); Ribosome biogenesis; Ubiquitin ligase; ZNRF3.