More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A +/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.

中文翻译：

---

KDM5A / RBP2组蛋白脱甲基酶抑制NOTCH信号传导，以维持神经内分泌分化并促进小细胞肺癌的肿瘤发生。

超过90％的小细胞肺癌（SCLC）在抑癌基因RB1中存在功能丧失突变。RB1基因产物pRB的典型功能是抑制E2F转录因子家族，但pRB的功能还包括通过与组蛋白脱甲基酶KDM5A（也称为RBP2或JARID1A）的结合来调节细胞分化。我们显示，KDM5A部分通过维持神经内分泌转录因子ASCL1的表达来促进SCLC增殖和SCLC的神经内分泌分化表型。从机制上讲，我们发现KDM5A通过抑制NOTCH2和NOTCH目标基因来维持ASCL1水平和神经内分泌分化。为了测试KDM5A在体内SCLC肿瘤发生中的作用，我们通过将表达针对Rb1，Tp53和Rbl2的Cre重组酶和sgRNA传递到Lox-Stop-Lox Cas9肺中的腺病毒（或腺相关病毒[AAV]），开发了基于CRISPR / Cas9的SCLC小鼠模型老鼠。与KDM5A + / + SCLC相比，KDM5A sgRNA的共包含可减少SCLC的肿瘤发生和转移，尽管不存在KDM5A，但形成的SCLC的NOTCH活性更高。这项工作确立了KDM5A在SCLC肿瘤发生中的作用，并建议应探索KDM5抑制剂作为SCLC的治疗方法。与KDM5A + / + SCLC相比，尽管不存在KDM5A，但形成的SCLC具有更高的NOTCH活性。这项工作确立了KDM5A在SCLC肿瘤发生中的作用，并建议应探索KDM5抑制剂作为SCLC的治疗方法。与KDM5A + / + SCLC相比，尽管不存在KDM5A，但形成的SCLC具有更高的NOTCH活性。这项工作确立了KDM5A在SCLC肿瘤发生中的作用，并建议应探索KDM5抑制剂作为SCLC的治疗方法。