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

Abstract

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d3475663e417">Neuroblastoma with <i>MYCN</i> 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. </p><div xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="fig panel" id="undfig1"> <a class="named-anchor" id="undfig1"> <!-- named anchor --> </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/656fe7b1-4f88-40ce-ada2-417fadedf8b2/PubMedCentral/image/fx1"/> </div> <div class="panel-content"/> </div><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d3475663e430"> <div class="list"> <a class="named-anchor" id="ulist0010"> <!-- named anchor --> </a> <ul class="so-custom-list" style="list-style-type: none"> <li id="u0010"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p dir="auto" id="p0010">MYCN promotes KDM4 induction and cellular state switch from mesenchymal to adrenergic</p> </div> </li> <li id="u0015"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p dir="auto" id="p0015">KDM4 inhibition induces H3K9me3 and blocks MYCN and adrenergic transcriptome</p> </div> </li> <li id="u0020"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p dir="auto" id="p0020">KDM4 inhibition leads to significant suppression of neuroblastoma growth</p> </div> </li> <li id="u0025"> <div class="so-custom-list-label so-ol">•</div> <div class="so-custom-list-content so-ol"> <p dir="auto" id="p0025">KDM4 inhibition in combination with chemotherapy results in complete tumor responses</p> </div> </li> </ul> </div> </p><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" dir="auto" id="d3475663e453">Abu-Zaid et al. show that KDM4 inhibition blocks MYCN function in high-risk neuroblastoma models. The combination of a selective KDM4 inhibitor with chemotherapy reduces tumor growth of neuroblastoma xenografts. </p>