Role of KDM5A in pRB-mediated differentiation

摘要 对最重要的肿瘤抑制基因之一RB 1的研究已经改变了 人类癌症的治疗这一成功是基于靶向E2 F反应 pRB功能失调直接导致基因失调。然而，在这方面， 有越来越多的证据表明，pRB的作用是多方面的， 细胞周期外过程的主要调节因子。特别是，我们重新发现了 第一个pRB相互作用的蛋白质，KDM 5A，在筛选对pRB至关重要的细胞因子 在分化过程中发挥作用。我们发现KDM 5A直接位于pRB的下游， 由于RB缺陷细胞中KDM 5A蛋白水平的降低， 重新引入pRB的影响：它增加了细胞类型特异性 转录因子，并恢复基因表达和形态学变化 与分化有关。KDM 5A是一种去甲基化酶， 在pRB靶基因的子集处从组蛋白H3（H3 K4）上的赖氨酸4甲基化。 令人惊讶的是，我们发现pRB功能在分化开始时收敛于 激活编码线粒体组分的KDM 5A靶基因。因此，委员会认为， Rb缺陷细胞中线粒体功能的主要调节因子的过表达， PGC-1α，恢复分化，表型复制pRB的重新引入。为了 机械地理解线粒体代谢调节和细胞周期之间的联系。 诱导分化，我们建议研究KDM 5A下游的RB途径： (1)我们将研究在函数中哪些函数是必要的和充分的 分化拯救;（2）我们将探索激活 RB缺陷型小细胞肺癌细胞中的线粒体功能;（3）我们将 研究pRB缺乏与线粒体损伤之间是否存在相关性。 签名，以及这与患者预后的关系;（4）我们将研究如何 线粒体基因受pRB、KDM 5A和相关转录因子的调控。 KDM 5A抑制与癌细胞代谢和分化的相关性是 KDM 5A可能是小分子抑制剂的靶点。

Abstract Studies of one of the most important tumor suppressor genes, RB1, have transformed the treatment of human cancer. This success was based on targeting E2F-responsive genes that were deregulated as a direct consequence of dysfunctional pRB. However, there is accumulating evidence of a multifaceted role of pRB and its involvement as a major regulator in processes outside the cell cycle. In particular, we rediscovered one of the first pRB-interacting proteins, KDM5A, in a screen for cellular factors critical for pRB function during differentiation. We found that KDM5A is directly downstream of pRB in the pathway, as decreasing KDM5A protein levels in RB-deficient cells was reminiscent of the effects of reintroducing pRB: it increased the activity of cell-type-specific transcription factors, and restored gene expression and morphological changes associated with differentiation. KDM5A is a demethylase that reads and removes methylation from lysine 4 on histone H3 (H3K4) at a subset of pRB target genes. Surprisingly, we found that pRB function at the onset of differentiation converges on activation of KDM5A target genes encoding mitochondrial components. Accordingly, overexpression in Rb-deficient cells of a major regulator of mitochondrial functions, PGC-1α, restored differentiation, phenocopying the reintroduction of pRB. In order to mechanistically understand the link between mitochondrial metabolic regulation and the induction of differentiation, we propose to study the RB pathway downstream of KDM5A: (1) we will investigate which functions in the mitochondrion are necessary and sufficient for differentiation rescue; (2) we will explore a therapeutic strategy for activation of mitochondrial function in cells from RB-deficient small cell lung cancers; (3) we will investigate whether there is a correlation between pRB deficiency and the mitochondrial signature, and how this relates to patient prognosis; and (4) we will study how mitochondrial genes are regulated by pRB, KDM5A and associated transcription factors. The relevance of KDM5A inhibition to cancer cell metabolism and differentiation is of great interest, as KDM5A is likely to be targeted by small-molecule inhibitors.