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Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer

Abstract

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 ATXN1LKO and CICKO 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.

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Acknowledgements

We thank Dr Gregory Cairncross, Dr Jennifer Chan, Dr Kenneth Aldape, Dr Severa Bunda, and members of the David Huntsman and Marco Marra laboratory for helpful discussions. SY is supported by a VCHRI mentored scientist award. MM acknowledges support from the Canada Research Chairs program and the Canadian Institutes of Health Research (CIHR; FDN-143288). We would also like to acknowledge the ongoing support from BrainCare BC, the BC Cancer Foundation, BC Cancer Agency, and the University of British Columbia. The results published here are in part based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov.

Funding

This work was funded by the BC Cancer Foundation (BCCF), the Vancouver Coastal Health Research Institute (VCHRI), and the Canadian Institutes for Health Research (CIHR).

Authors contributions

DW and SY conceived and designed the study. The manuscript was written by DW and SY with support from VL. DW performed the TCGA bioinformatic analyses with guidance from VL. DW, AL and KL developed and validated the ATXN1LKO CRISPR cell lines. JS and SYC developed and validated the CICKO CRISPR cell lines. DW performed most of the cell-based assays with contributions from KL. SY supervised the project with further guidance from SC and MM. All authors participated in discussions regarding experiment design and results, and have reviewed and approved the data and manuscript.

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Correspondence to Stephen Yip.

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Wong, D., Lounsbury, K., Lum, A. et al. Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer. Oncogene 38, 273–290 (2019). https://doi.org/10.1038/s41388-018-0427-5

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