Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through activation of the MAPK signalling cascade and derepression of oncogenic ETS transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in developmental and disease contexts to facilitate the repression of CIC target genes. To further investigate this relationship, we performed functional in vitro studies utilizing ATXN1L and CIC human cell lines and characterized a reciprocal functional relationship between CIC and ATXN1L. Transcriptomic interrogation of the CIC-ATXN1-ATXN1L axis in low-grade glioma, prostate adenocarcinoma and stomach adenocarcinoma TCGA cohorts revealed context-dependent convergence of gene sets and pathways related to mitotic cell cycle and division. This study highlights the CIC-ATXN1-ATXN1L axis as a more potent regulator of the cell cycle than previously appreciated.
NEURO-ONCOLOGY • NOVEMBER 2017 culture counting and ATPlite assays we found the WT+ and NP lines to have a significant (P< 0.01) decrease in growth compared to control and PP mutant. This was further supported by knockdown of MARCKS in a high expressing patient derived xenograft (PDX) line XD456 which resulted in increased neurosphere formation in a limiting dilution assay and increased cell growth by cell titer glow. We also found radiation sensitivity to enhance in the WT and NP expressing lines through a combination of clonogenic, comet and gamma-H2AX foci formation assays. Through orthotopic implantation of our MARCKS ED mutants into athymic nude mice, we saw a significant (P<0.05) survival benefit and increased response to radiation in our WT+ line with 6 Gy total dose delivered (2 Gy, 3X in a week). Overall, MARCKS phosphorylation alters its tumor suppressive effects.
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