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Merck
  • Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Cell reports. Medicine (2024-03-21)
Ahmed Abu-Zaid, Jie Fang, Hongjian Jin, Shivendra Singh, Prahalathan Pichavaram, Qiong Wu, Heather Tillman, Laura Janke, Wojciech Rosikiewicz, Beisi Xu, Lee-Ann Van De Velde, Yian Guo, Yimei Li, Noha A M Shendy, Ian M Delahunty, Zoran Rankovic, Taosheng Chen, Xiang Chen, Kevin W Freeman, Mark E Hatley, Adam D Durbin, Peter J Murray, Andrew J Murphy, Paul G Thomas, Andrew M Davidoff, Jun Yang
摘要

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

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Sigma-Aldrich
抗肌动蛋白抗体 兔抗, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-KDM4A antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-KDM4C antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody