JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

Abstract

Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9);

R1 Regulates Prostate Tumor Growth and Progression By Transcriptional Suppression of the E3 Ligase HUWE1 to Stabilize c-Myc

“…Although R1 was first identified as a c-Myc oncoprotein interactor, little progress has been made so far in understanding its role in cancer in general and in prostate cancer specifically. Previous studies showed that R1 enhances medulloblastoma transformation with induced aggressive phenotypes (11,39) and also hepatocellular carcinoma progression (40). Our results obtained from prostate cancer are consistent with those observations, further supporting a tumor-promoting effect of R1 in cancers.…”

“…These accumulated gene and pathway profiles lay the mechanistic foundations for identifying potential R1-interacting factors, given the intimate regulatory relationship between R1 and c-Myc demonstrated by other groups and by us. This idea has been coincidentally supported by recent findings of AKT activation by R1 in medulloblastoma (39). Future studies exploring the gene and signaling networks governed by R1 are merited to uncover potential unknown functions of R1 in prostate cancer.…”

“…R1 forms a ternary complex with transcription coactivator LEDGF/p75 and chromatin in transcriptional regulation, which may contribute to the development of MLL fusiondriven acute leukemia (14,49). In medulloblastoma, the cooperation of R1 with LEDGF/p75 also promotes cell migration and metastasis by activation of AKT signaling (39). However, the direct suppressing effect of R1 by serving as a transcription repressor on MAOA gene expression, which was first demonstrated in neuroblastoma cells, turns out to be marginal in prostate cancer, leading to activation of MAOA (13,50).…”

Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation

“…In addition to HIV integrase, a diverse network of physiological IBD interaction partners has been discovered, including the PI3K regulator JPO2 (CDCA7L) (11)(12)(13), the zinc-finger protein POGZ (14), the cell-cycle regulator ASK (DBF4) (15), the MLL1-MENIN binary complex (16), and the transcription elongation regulator IWS1 (17). We previously revealed that all known cellular partners of the LEDGF/p75 IBD contain an intrinsically disordered IBD-binding motif (IBM) (17,18).…”

The therapeutic potential of targeting the PI3K pathway in pediatric brain tumors

“…Amplification of AKT3 has also been identified [81]. Additionally, a recent study demonstrated that Myc induced PI3K signaling drove a metastatic phenotype in orthotopic models [82]. …”