PT  - JOURNAL ARTICLE
AU  - Xu, Man
AU  - Sun, Ming
AU  - Zhang, Xiyuan
AU  - Nguyen, Rosa
AU  - Lei, Haiyan
AU  - Shern, Jack F.
AU  - Thiele, Carol J.
AU  - Liu, Zhihui
TI  - A “<em>cooperative collaboration</em>” between HAND2 and MYCN shapes neuroblastoma cell identity
AID  - 10.1101/2022.05.18.492511
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.18.492511
4099  - http://biorxiv.org/content/early/2022/05/20/2022.05.18.492511.short
4100  - http://biorxiv.org/content/early/2022/05/20/2022.05.18.492511.full
AB  - Noradrenergic neuroblastoma (NB) is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TFs) such as PHOX2B, HAND2 and GATA3, which form a network with MYCN. Physiological levels of MYCN mainly binds to promoters but aberrantly upregulated MYCN in NB also binds to enhancers. How MYCN invades enhancers, and what role the CRC TFs play in this process is unknown. Here we find that HAND2 assists MYCN to invade enhancers through an “indirect cooperative” TF-DNA binding mechanism. HAND2 cooperates with MYCN to compete with nucleosomes and regulate global gene transcription. The treatment of NB with an Aurora A kinase inhibitor plus HDAC inhibitor potently downregulates both MYCN and the CRC TFs and suppresses MYCN-amplified NB tumor growth. Our study identifies a “cooperative collaboration” among MYCN and CRC TFs and the simultaneous targeting these TFs is an effective way to treat this aggressive pediatric tumor.Competing Interest StatementThe authors have declared no competing interest.