Liu Rui, Li Zongwei, Chen Rui, Fang Zhihong, Liu Zhiqiang, Liu Huan
Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China.
School of Life Sciences, Anhui Medical University, Hefei, Anhui, China.
Nat Commun. 2025 Jan 31;16(1):1206. doi: 10.1038/s41467-025-56506-5.
Myelomatous bone disease is a complication characterized by lytic bone lesions, reduced bone formation, bone pain, and increased fracture risk. Understanding these underlying mechanisms is crucial for developing effective therapeutic approaches. Here we show the role of enhancer of zeste homolog 2 (EZH2) in bone lesions induced by myeloma cells. Our research reveals that cytokines produced by myeloma-associated adipocytes activate the expression of EZH2 in myeloma cells. Furthermore, we find that EZH2 forms a transcriptional repression complex with transcription factor AP2α. This complex promotes trimethylation at lysine 27 of histone H3 (H3K27me3) in the promoter region of the tumor suppressor gene EMP1, resulting in transcriptional silencing. EMP1 silencing leads to increased myeloma cell proliferation and the concomitant secretion of osteolytic cytokines that contribute to bone destruction. Importantly, EZH2 inhibitors effectively treat myeloma-induced osteolytic lesions. Thus, targeting EZH2 represents a potential therapeutic strategy for preventing and managing myeloma bone disease.
骨髓瘤性骨病是一种并发症，其特征为溶骨性骨病变、骨形成减少、骨痛和骨折风险增加。了解这些潜在机制对于开发有效的治疗方法至关重要。在此，我们展示了zeste同源物2（EZH2）在骨髓瘤细胞诱导的骨病变中的作用。我们的研究表明，骨髓瘤相关脂肪细胞产生的细胞因子激活了骨髓瘤细胞中EZH2的表达。此外，我们发现EZH2与转录因子AP2α形成转录抑制复合物。该复合物促进肿瘤抑制基因EMP1启动子区域组蛋白H3赖氨酸27（H3K27me3）的三甲基化，导致转录沉默。EMP1沉默导致骨髓瘤细胞增殖增加以及伴随的溶骨细胞因子分泌增加，从而导致骨破坏。重要的是，EZH2抑制剂可有效治疗骨髓瘤诱导的溶骨性病变。因此，靶向EZH2代表了一种预防和管理骨髓瘤性骨病的潜在治疗策略。
