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. 2022 Jun 6;2(6):402–416. doi: 10.1158/2767-9764.CRC-22-0124

FIGURE 6.

FIGURE 6

Increased proteasome activity in SMOi-resistant SI-CSC tumors degrade GCN5 and CBP. Histone acetyltransferase Crebbp/CBP level is not altered at the RNA level (A) but is significantly reduced at the protein level (B). Also see Fig. 4 A and B. C, Significant enrichment of the Proteasome pathway geneset in proteomics dataset in Ptch;p53 SMOi-resistant SI-CSC medulloblastoma. D, LDE-resistant SI-CSC cells treated with cycloheximide (CHX) show shortened half-life of CBP and GCN5 proteins compared with control. E, Proteasome-Glo assay shows increased proteasomal activity in LDE-resistant SI-CSC cells. N = 6, ***P < 0.0001, by two-tailed Student t test. F, Treatment with a proteasome inhibitor, MG132, shows significant recovery of CBP and GCN5 proteirn levels in LDE-resistant SI-CSC cells. G, CBP and GCN5 protein levels are unchanged in response to acute (24 hours) LDE treatment in fSmoM2;hGFAPcre tumorsphere cells in vitro. H, A working model of epigenetically reprogrammed therapy resistance in SI-CSCs medulloblastomas.