Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Korea.
Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea.
Sci Rep. 2024 Mar 21;14(1):6764. doi: 10.1038/s41598-024-55113-6.
EBV-infected lymphoma has a poor prognosis and various treatment strategies are being explored. Reports suggesting that B cell lymphoma can be induced by epigenetic regulation have piqued interest in studying mechanisms targeting epigenetic regulation. Here, we set out to identify an epigenetic regulator drug that acts synergistically with doxorubicin in EBV-positive lymphoma. We expressed the major EBV protein, LMP1, in B-cell lymphoma cell lines and used them to screen 100 epigenetic modifiers in combination with doxorubicin. The screening results identified TCP, which is an inhibitor of LSD1. Further analyses revealed that LMP1 increased the activity of LSD1 to enhance stemness ability under doxorubicin treatment, as evidenced by colony-forming and ALDEFLUOR activity assays. Quantseq 3' mRNA sequencing analysis of potential targets regulated by LSD1 in modulating stemness revealed that the LMP1-induced upregulation of CHAC2 was decreased when LSD1 was inhibited by TCP or downregulated by siRNA. We further observed that SOX2 expression was altered in response to CHAC2 expression, suggesting that stemness is regulated. Collectively, these findings suggest that LSD1 inhibitors could serve as promising therapeutic candidates for EBV-positive lymphoma, potentially reducing stemness activity when combined with conventional drugs to offer an effective treatment approach.
EBV 感染的淋巴瘤预后不良，目前正在探索各种治疗策略。有报道称，表观遗传调控可诱导 B 细胞淋巴瘤，这激发了人们对研究针对表观遗传调控机制的兴趣。在这里，我们旨在确定一种与阿霉素协同作用于 EBV 阳性淋巴瘤的表观遗传调节剂药物。我们在 B 细胞淋巴瘤细胞系中表达主要 EBV 蛋白 LMP1，并使用它们筛选与阿霉素联合作用的 100 种表观遗传修饰剂。筛选结果鉴定出 TCP，它是 LSD1 的抑制剂。进一步分析表明，LMP1 在阿霉素处理下增加 LSD1 的活性，从而增强干性能力，这可以通过集落形成和 ALDEFLUOR 活性测定来证明。定量测序 3' mRNA 测序分析 LSD1 调节干性的潜在靶标表明，当 LSD1 被 TCP 抑制或通过 siRNA 下调时，LMP1 诱导的 CHAC2 上调减少。我们进一步观察到 SOX2 表达响应 CHAC2 表达而改变，表明干性受到调节。总的来说，这些发现表明 LSD1 抑制剂可能成为 EBV 阳性淋巴瘤有前途的治疗候选药物，当与传统药物联合使用时，可能会降低干性活性，提供有效的治疗方法。
