Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell-like Properties in Osteosarcoma
Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell-like Properties in Osteosarcoma
复制标题
表观遗传分析确定 LIF 是骨肉瘤中干细胞样特性的超级增强子控制调节剂
DOI：
10.1158/1541-7786.mcr-19-0470
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发表时间：
2020-01-01
影响因子：
5.2
通讯作者：
Zhao, Wei
中科院分区：
文献类型：
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作者：
Lu, Bing;He, Yangyang;Zhao, Wei
骨肉瘤是一种侵袭性强、预后差的恶性肿瘤。超级增强子（SE）已被强调为维持癌细胞特性所需的关键致癌元件。然而，SEs在骨肉瘤性质中的调节作用尚未阐明。在目前的研究中，我们发现，骨肉瘤细胞和临床标本共享一个显着的比例SE。此外，白血病抑制因子（LIF）被确定为骨肉瘤特异性SE控制下的必需因子。骨肉瘤中LIF的表达与干细胞核心因子基因的表达呈正相关。此外，LIF重组蛋白处理的骨肉瘤细胞表现出增强的干细胞样特征，如增加球体形成潜力，刺激自我更新，上调转移能力，并增加干细胞相关基因表达。值得注意的是，组蛋白3赖氨酸27三甲基化（H3 K27 me 3）去甲基化酶UTX被发现是骨肉瘤中LIF转录的关键激活因子。UTX抑制剂GSK-J 4诱导H3 K27 me 3积累并损害LIF基因位点的组蛋白3赖氨酸27乙酰化（H3 K27 ac），导致LIF信号通路抑制。GSK-J 4治疗通过调节NOTCH 1信号通路基因位点的H3 K27 ac导致骨肉瘤中干细胞样特征和干细胞相关基因激活的严重缺陷。NOTCH 1抑制剂Crenigacestat（TargetMol，T3633）抑制LIF介导的骨肉瘤患者源性原发组织中干细胞相关基因的激活。
Osteosarcoma is an aggressive malignancy with poor prognosis. Super-enhancers (SE) have been highlighted as critical oncogenic elements required for maintaining the cancer cell characteristics. However, the regulatory role of SEs in osteosarcoma properties has not yet been elucidated. In the current study, we found that osteosarcoma cells and clinical specimens shared a significant fraction of SEs. Moreover, leukemia-inhibitory factor (LIF) was identified as an essential factor under the control of osteosarcoma-specific SE. The expression of LIF was positively correlated with the stem cell core factor genes in osteosarcoma. Furthermore, LIF recombinant protein-treated osteosarcoma cells displayed enhanced stem cell-like characteristics, such as increased sphere-forming potential, stimulated self-renewal, upregulated metastasis ability, and increased stemness-related gene expression. Notably, the histone 3 lysine 27 tri-methylation (H3K27me3) demethylase UTX was found as a key activator of LIF transcription in osteosarcoma. The UTX inhibitor, GSK-J4, induced H3K27me3 accumulation and impaired histone 3 lysine 27 acetylation (H3K27ac) at LIF gene locus, leading to LIF signaling pathway inhibition. GSK-J4 treatment resulted in profound defects in stem cell-like characteristics and stemness-related gene activation in osteosarcoma by modulating the H3K27ac of NOTCH1 signaling pathway gene loci. The NOTCH1 inhibitor Crenigacestat (TargetMol, T3633) repressed LIF-mediated activation of the stemness-related genes in osteosarcoma patient-derived primary tissues.