Mechanistic insights into KDM4A driven genomic instability.
Mechanistic insights into KDM4A driven genomic instability.
复制标题
DOI：
10.1042/bst20191219
复制
发表时间：
2021-02-26
影响因子：
3.9
通讯作者：
Dere R
中科院分区：
文献类型：
--
作者：
Young NL;Dere R
染色质上的整体表观遗传特征的改变被充分确立为有助于肿瘤的发生和进展。染色质甲基化状态调节维持基因组完整性的几个关键细胞过程。KDM 4A是一种脱甲基酶，属于Fe-II依赖性双加氧酶家族，使用α-酮戊二酸和分子氧作为辅因子，在几种癌症中过表达，并与总体预后不良相关。KDM 4A使组蛋白H3上的赖氨酸9（H3 K9 me 2/3）和赖氨酸36（H3 K36 me 3）甲基标记去甲基化。考虑到染色质上这些标记的复杂性及其对转录和增殖的影响，自然可以得出去甲基化在这些细胞过程中起着同样重要的作用。在这篇综述中，我们强调了KDM 4A在转录调节中的作用，无论是依赖于或独立于其酶活性，产生于这种去甲基化酶在癌症中的扩增。KDM 4A调节不同基因组基因座的再复制，激活细胞周期诱导剂，并抑制参与检查点控制的蛋白质，从而引起增殖性损伤、有丝分裂紊乱和染色体断裂，最终导致基因组不稳定。与此同时，表观遗传调节剂的非核底物的新证据强调需要研究KDM 4A在调节非核底物中的作用，并评估其对基因组不稳定性的贡献。有前途的KDM特异性抑制剂的存在使得这些去甲基化酶成为癌症治疗干预的有吸引力的靶点。
Alterations in global epigenetic signatures on chromatin are well established to contribute to tumor initiation and progression. Chromatin methylation status modulates several key cellular processes that maintain the integrity of the genome. KDM4A, a demethylase that belongs to the Fe-II dependent dioxygenase family that uses α-ketoglutarate and molecular oxygen as cofactors, is overexpressed in several cancers and is associated with an overall poor prognosis. KDM4A demethylates lysine 9 (H3K9me2/3) and lysine 36 (H3K36me3) methyl marks on histone H3. Given the complexity that exists with these marks on chromatin and their effects on transcription and proliferation, it naturally follows that demethylation serves an equally important role in these cellular processes. In this review, we highlight the role of KDM4A in transcriptional modulation, either dependent or independent of its enzymatic activity, arising from the amplification of this demethylase in cancer. KDM4A modulates re-replication of distinct genomic loci, activates cell cycle inducers, and represses proteins involved in checkpoint control giving rise to proliferative damage, mitotic disturbances and chromosomal breaks, ultimately resulting in genomic instability. In parallel, emerging evidence of non-nuclear substrates of epigenetic modulators emphasize the need to investigate the role of KDM4A in regulating non-nuclear substrates and evaluate their contribution to genomic instability in this context. The existence of promising KDM-specific inhibitors makes these demethylases an attractive target for therapeutic intervention in cancers.