Theranostics 2019; 9(4):986-1000. doi:10.7150/thno.30199

Research Paper

Collaborative ISL1/GATA3 interaction in controlling neuroblastoma oncogenic pathways overlapping with but distinct from MYCN

Qitong Zhang1*, Qingquan Zhang1*, Xue Jiang1, Youqiong Ye2, Huimin Liao1, Fugui Zhu2, Jie Yan1, Lina Luo1, Li Tian3, Cizhong Jiang2, Yihan Chen1, Xingqun Liang1,✉, Yunfu Sun1,✉

1. Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China.
2. School of Life Sciences and Technology, Tongji University, Shanghai, China.
3. Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, Tartu 50411, ESTONIA
* These authors contributed equally to this work

Abstract

Background: Transcription factor ISL1 plays a critical role in sympathetic neurogenesis. Expression of ISL1 has been associated with neuroblastoma, a pediatric tumor derived from sympatho-adrenal progenitors, however the role of ISL1 in neuroblastoma remains unexplored.

Method: Here, we knocked down ISL1 (KD) in SH-SY5Y neuroblastoma cells and performed RNA-seq and ISL1 ChIP-seq analyses.

Results: Analyses of these data revealed that ISL1 acts upstream of multiple oncogenic genes and pathways essential for neuroblastoma proliferation and differentiation, including LMO1 and LIN28B. ISL1 promotes expression of a number of cell cycle associated genes, but represses differentiation associated genes including RA receptors and the downstream target genes EPAS1 and CDKN1A. Consequently, Knockdown of ISL1 inhibits neuroblastoma cell proliferation and migration in vitro and impedes tumor growth in vivo, and enhances neuronal differentiation by RA treatment. Furthermore, genome-wide mapping revealed a substantial co-occupancy of binding regions by ISL1 and GATA3, and ISL1 physically interacts with GATA3, and together they synergistically regulate the aforementioned oncogenic pathways. In addition, analyses of the roles of ISL1 and MYCN in MYCN-amplified and MYCN non-amplified neuroblastoma cells revealed an epistatic relationship between ISL1 and MYCN. ISL1 and MYCN function in parallel to regulate common yet distinct oncogenic pathways in neuroblastoma.

Conclusion: Our study has demonstrated that ISL1 plays an essential role in neuroblastoma regulatory networks and may serve as a potential therapeutic target in neuroblastoma.

Keywords: neuroblastoma, ISL1, GATA3, RA signaling, genetic pathways

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How to cite this article:
Zhang Q, Zhang Q, Jiang X, Ye Y, Liao H, Zhu F, Yan J, Luo L, Tian L, Jiang C, Chen Y, Liang X, Sun Y. Collaborative ISL1/GATA3 interaction in controlling neuroblastoma oncogenic pathways overlapping with but distinct from MYCN. Theranostics 2019; 9(4):986-1000. doi:10.7150/thno.30199. Available from http://www.thno.org/v09p0986.htm