作者: Osaki, Yosuke ; Maeda, Kazuya ; Hara, Daisuke ; Nakashima, Ayumu ; Masaki, Takao ; Doi, Shigehiro ; Ishiuchi, Naoki ; Ike, Takeshi ; Takahashi, Akira ; Chiba, Takuto ; Yoshida, Maria ; Maeoka, Yujiro ; Doi, Toshiki ; Sasaki, Kensuke

ABSTRACTPeritoneal fibrosis poses a significant challenge to the long‐term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting the role of cellular senescence in its pathogenesis. p16INK4a is a cell cycle regulator that has been implicated in cellular senescence. Mixed‐lineage leukemia 1 (MLL1) forms a complex with WD‐40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown that inhibition of the MLL1/WDR5 complex reduces p16INK4a expression and attenuates renal senescence after injury in mice. This study aimed to investigate whether inhibiting MLL1/WDR5 attenuates peritoneal senescence, inflammation, and fibrosis in both human samples and in mice with methylglyoxal (MGO)‐induced peritoneal fibrosis (MGO‐injected mice), while also exploring the associated underlying mechanisms. MLL1/WDR5, histone 3 lysine 4 trimethylation (H3K4me3), and p16INK4a expression were elevated in TGF‐β1‐stimulated human peritoneal mesothelial cells (HPMCs), non‐adherent cells obtained from patients undergoing PD, and the submesothelial compact zones of MGO‐injected mice. Notably, p16INK4a expression in these cells was positively correlated with the dialysate/plasma creatinine ratio. Treatment with the MLL1/WDR5 protein–protein interaction inhibitors MM‐102 and OICR‐9429 reduced H3K4me3 levels and p16INK4a expression, suppressing fibrosis in HPMCs as well as peritoneal fibrosis and inflammation in MGO‐injected mice. These inhibitors also improved peritoneal function in MGO‐injected mice. Additionally, we demonstrated that MLL1/WDR5‐induced H3K4me3 directly regulates p16INK4a gene transcription, and that inhibiting MLL1/WDR5 reduces H3K4me3, thereby suppressing p16INK4a gene transcription. These findings suggest that targeting MLL1/WDR5 activation alleviates peritoneal senescence, inflammation, and fibrosis, highlighting its potential as a promising therapeutic strategy for peritoneal fibrosis.

2025-04-01·Biochemical and Biophysical Research Communications

Inhibition of the MLL1-WDR5 interaction modulates epithelial to mesenchymal transition and metabolic pathways in triple-negative breast cancer cells

Article

作者: Sarkar, Shilpi ; Kandasamy, Thirukumaran ; Ghosh, Siddhartha Sankar

Histone methylation is a key epigenetic modulation that regulates gene expression and is often associated with the pathogenesis of various cancers, including triple-negative breast cancer (TNBC). Histone methyltransferase, MLL1-WDR5 complex regulates gene transcription by catalyzing trimethylation of lysine 4 on histone H3 (H3K4me3) and promotes carcinogenesis. Herein, epithelial-to-mesenchymal transition (EMT) in TNBC cells is shown to facilitate upregulation of MLL1 and WDR5 expression by 4.7-fold and 3.84-fold, thereby establishing the association of these proteins in EMT dynamics. Therefore, we explored the therapeutic potential of inhibiting MLL1-WDR5 interaction using the small molecule inhibitor MM-102 in TNBC cell lines. MLL1 inhibition significantly reduced H3K4me3 levels and enhanced the apoptotic population by 30 % in MDA-MB-468 cells, demonstrating its cytotoxic potential. Notably, MM-102 treatment reverses the EMT process by upregulating the expression of epithelial markers (such as E-cadherin and claudin) and downregulating the expression of mesenchymal markers (such as β-catenin, Slug, caveolin 1, and fibronectin). In addition, MLL1 inhibition caused a metabolic shift, with a 5-fold increase in ALDO A and a 4-fold increase in ENO1 expression, indicating enhanced glycolysis. Further reduction in the fatty acid uptake and lipid droplet accumulation by MM-102 treatment signifies that targeting MLL1 also rewires the metabolic network in TNBC cells. Collectively, inhibiting MLL1 represents a promising therapeutic strategy for managing EMT-driven metastasis, reshaping metabolic reprogramming, and ultimately improving therapeutic outcomes in aggressive breast cancer.

2025-01-23·Journal of Medicinal Chemistry

Discovery of WDR5–MLL1 and HDAC Dual-Target Inhibitors for the Treatment of Acute Myeloid Leukemia

Article

作者: Chen, Xin ; Sun, Liangkui ; You, Qidong ; Long, Guanlu ; Wang, Xianghan ; Guo, Xiaoke ; Ma, Sai ; Jiang, Zhengyu

Targeting the WDR5-MLL1 protein-protein interaction (PPI) is considered to be an effective approach for the treatment of MLL-rearranged leukemia. However, interfering with WDR5-MLL1 PPI reduces methylated H3K4 levels and induces a decline in acetylated H3 levels, which may contribute to the suboptimal cellular efficacy of WDR5 inhibitors. We observed that cotreatment with WDR5-MLL1 PPI and HDAC inhibitors augmented the antiproliferative effect in MV-4-11 cells. Thus, a series of dual-target inhibitors was developed by merging the pharmacophores of the WDR5 and HDAC inhibitors. Among the developed inhibitors, compound 32d displayed an 89-fold increase in antiproliferative efficacy and induced potent cell apoptosis by impeding the DNA damage repair signaling pathway. Furthermore, the administration of 30 mg/kg of compound 32d was well tolerated, inhibiting MV-4-11 xenograft growth by 87.1%. Our investigation established the therapeutic effectiveness of the developed WDR5-MLL1/HDAC dual-target inhibitor against acute myeloid leukemia, providing a valuable tool for further exploration of crosstalk between the two targets.

项与 WDR5 x MLL1 相关的新闻（医药）

2022-09-15

·生物谷

iScience：陈勇团队揭示DPY30促进MLL复合物甲基转移酶活性的分子机制

H3K4甲基化修饰对增强子活性调控、转录激活和细胞命运决定起关键作用，其异常会导致多种白血病和恶性肿瘤的发生。H3K4甲基化修饰主要是由MLL家族蛋白催化产生。 H3K4甲基化修饰对增强子活性调控、转录激活和细胞命运决定起关键作用，其异常会导致多种白血病和恶性肿瘤的发生。H3K4甲基化修饰主要是由MLL家族蛋白催化产生。MLL家族蛋白自身的甲基转移酶活性很低，需要与WDR5、RBBP5、ASH2L、DPY30等调节亚基形成复合物，才能有效发挥酶活。WDR5、RBBP5、ASH2L等亚基参与调控MLL蛋白酶活的分子机制在过去得到了充分的研究，但DPY30作为复合物中最小的蛋白（只有99个氨基酸）其发挥的作用和调节机制尚不明确。近日，中国科学院分子细胞科学卓越创新中心（生物化学与细胞生物学研究所）陈勇研究组在 iScience 期刊发表了题为：DPY30 acts as an ASH2L-specific stabilizer to stimulate the enzyme activity of MLL family methyltransferases on different substrates 的研究论文，揭示了DPY30促进MLL复合物甲基转移酶活性的分子机制。在这项研究中，研究团队发现DPY30可以不同程度地增强MLL1复合物在不同底物上的活性。在核小体底物上，DPY30能提高MLL复合物的催化效率逾27倍；在组蛋白多肽、H3或组蛋白八聚体水平上，DPY30仅能提高催化效率约1.8倍。研究团队继而通过交联质谱、小角散射、结构预测、动力学模拟等多种方法阐明了DPY30通过多种机制来调控复合物的甲基转移酶活性。首先，DPY30与ASH2L的多个结构域结合，增加了ASH2L的结构紧致性和热稳定性；DPY30稳定后的ASH2L与RBBP5结合力增强，促进MLL1复合物组装形成一个更紧凑和更稳定的复合物，导致DPY30可以微调MLL1复合物在组蛋白多肽、H3、组蛋白八聚体上的酶活。其次，DPY30稳定后的ASH2L获得了与组蛋白H3 N端尾巴（1-40）和核小体DNA结合的新的作用界面，确保核小体H3的尾部准确且稳定地进入MLLSET的催化口袋，从而极大地促进MLL1复合物甲基化核小体的活性，揭示了DPY30特异性促进MLL1复合物在核小体上酶活的机制。 DPY30促进MLL复合物甲基转移酶活性的分子机制 DPY30在多种癌症中高表达，之前的研究表明DPY30的促癌效应与H3K4甲基化修饰相关。在癌细胞中敲低DPY30，H3K4甲基化修饰水平降低，癌细胞增殖减慢；回补DPY30，H3K4甲基化修饰水平增加，癌细胞增殖增快。因此，该研究中揭示的DPY30调控MLL复合物甲基转移酶活性的分子机制可以为理解相关癌症发病机制提供理论基础，以及为相关癌症的治疗提供新的设计思路和设计靶点。中科院分子细胞卓越中心博士生赵利杰为论文第一作者，陈勇研究员为该论文的通讯作者。该研究工作获得中科院战略性先导计划和国家自然科学基金委的经费资助。该研究得到张江实验室国家蛋白质科学研究（上海）设施BL19U2小角散射线站、质谱分析系统和规模化蛋白质制备系统的支持和帮助。

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