Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, 215123, Suzhou, Jiangsu, China.
Institute of Aging & Tissue Regeneration, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 200127, Shanghai, China.
Cell Death Dis. 2024 May 14;15(5):335. doi: 10.1038/s41419-024-06714-6.
PTENα/β, two variants of PTEN, play a key role in promoting tumor growth by interacting with WDR5 through their N-terminal extensions (NTEs). This interaction facilitates the recruitment of the SET1/MLL methyltransferase complex, resulting in histone H3K4 trimethylation and upregulation of oncogenes such as NOTCH3, which in turn promotes tumor growth. However, the molecular mechanism underlying this interaction has remained elusive. In this study, we determined the first crystal structure of PTENα-NTE in complex with WDR5, which reveals that PTENα utilizes a unique binding motif of a sequence SSSRRSS found in the NTE domain of PTENα/β to specifically bind to the WIN site of WDR5. Disruption of this interaction significantly impedes cell proliferation and tumor growth, highlighting the potential of the WIN site inhibitors of WDR5 as a way of therapeutic intervention of the PTENα/β associated cancers. These findings not only shed light on the important role of the PTENα/β-WDR5 interaction in carcinogenesis, but also present a promising avenue for developing cancer treatments that target this pathway.
PTENα/β，PTEN 的两种变体，通过其 N 端延伸（NTE）与 WDR5 相互作用，在促进肿瘤生长中发挥关键作用。这种相互作用促进了 SET1/MLL 甲基转移酶复合物的募集，导致组蛋白 H3K4 三甲基化和致癌基因如 NOTCH3 的上调，进而促进肿瘤生长。然而，这种相互作用的分子机制仍然难以捉摸。在这项研究中，我们确定了 PTENα-NTE 与 WDR5 复合物的第一个晶体结构，该结构揭示了 PTENα 利用在 PTENα/β 的 NTE 结构域中发现的独特的序列 SSSRRSS 结合基序特异性结合到 WDR5 的 WIN 位点。破坏这种相互作用会显著阻碍细胞增殖和肿瘤生长，突出了 WDR5 的 WIN 位点抑制剂作为治疗干预与 PTENα/β 相关癌症的潜在途径。这些发现不仅揭示了 PTENα/β-WDR5 相互作用在致癌作用中的重要作用，而且为开发针对该途径的癌症治疗方法提供了有前途的途径。
