YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells

Abstract

Post-natal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the SHH-associated subgroup of medulloblastoma (MB), is driven by Sonic Hedgehog (Shh) and Insulin-like Growth Factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is up-regulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh-subgroup of MB in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and medulloblastoma cells and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.

Y‐box binding protein‐1 promotes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma

“…Cell growth is strictly regulated and controlled by a careful balance of regulatory systems. Abnormal cell growth is the critical feature of malignant tumors . In this study, we observed a significant suppression of cell proliferation of chordoma cell lines after YBX1 knockdown, consistent with previous studies.…”

miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1

“…For example, human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway 23 and the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas. 24 Also,YB-1 associates with thousands of nonpolyadenylated short RNAs (shyRNAs) that are further processed into small RNAs (smyRNAs). 25 Moreover, ENZ-induced HER2 overexpression was dependent on AKT-YB1 activation and modulated AR activity.…”

Dual roles of yes-associated protein (YAP) in colorectal cancer

“…Recent studies have demonstrated that the Hippo/YAP pathway can crosstalk with other signalling pathways to regulate a series of biological functions in cancer, which is greatly depends on the important role of YAP that is not only mediated by the upstream signal molecule, but can also regulate a series of targets via interacting with transcription factors. By analysing studies published in recent years, we can summarize a complex regulatory network in which YAP is involved in a series of signalling pathways (Figure 1 ), such as those involving TGF-β/SMAD [ 67 , 68 ], Wnt/β-catenin [ 69 , 70 ], epidermal growth factor receptor (EGFR) [ 39 , 71 ], PI3K-AKT [ 72 , 73 ], NF-κB [ 69 , 74 ], Sonic Hedgehog (Shh) [ 75 , 76 ], mTOR [ 77 , 78 ], IL6 receptor (IL-6R) [ 79 , 80 ], GPCR [ 81 , 82 ], and Notch [ 83 , 84 ].…”