Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
Oncogene. 2022 May;41(21):2958-2972. doi: 10.1038/s41388-022-02311-z. Epub 2022 Apr 19.
The H3K4 demethylase KDM5B is overexpressed in multiple cancer types, and elevated expression levels of KDM5B is associated with decreased survival. However, the underlying mechanistic contribution of dysregulated expression of KDM5B and H3K4 demethylation in cancer is poorly understood. Our results show that loss of KDM5B in multiple types of cancer cells leads to increased proliferation and elevated expression of cancer stem cell markers. In addition, we observed enhanced tumor formation following KDM5B depletion in a subset of representative cancer cell lines. Our findings also support a role for KDM5B in regulating epigenetic plasticity, where loss of KDM5B in cancer cells with elevated KDM5B expression leads to alterations in activity of chromatin states, which facilitate activation or repression of alternative transcriptional programs. In addition, we define KDM5B-centric epigenetic and transcriptional patterns that support cancer cell plasticity, where KDM5B depleted cancer cells exhibit altered epigenetic and transcriptional profiles resembling a more primitive cellular state. This study also provides a resource for evaluating associations between alterations in epigenetic patterning upon depletion of KDM5B and gene expression in a diverse set of cancer cells.
H3K4 去甲基化酶 KDM5B 在多种癌症类型中过表达，并且 KDM5B 的高表达水平与存活率降低有关。然而，KDM5B 的表达失调和 H3K4 去甲基化在癌症中的潜在机制贡献还了解甚少。我们的结果表明，多种类型的癌细胞中 KDM5B 的缺失导致增殖增加和癌症干细胞标志物的表达升高。此外，我们观察到在一组代表性癌细胞系中 KDM5B 耗竭后肿瘤形成增强。我们的研究结果还支持 KDM5B 在调节表观遗传可塑性中的作用，在高表达 KDM5B 的癌细胞中 KDM5B 的缺失导致染色质状态活性的改变，从而促进替代转录程序的激活或抑制。此外，我们定义了以 KDM5B 为中心的表观遗传和转录模式，支持癌细胞可塑性，其中 KDM5B 耗尽的癌细胞表现出改变的表观遗传和转录特征，类似于更原始的细胞状态。这项研究还为评估在一组多样化的癌细胞中 KDM5B 耗竭后表观遗传模式的改变与基因表达之间的关联提供了资源。
