Li Zhanhu, Chen Dong
Department of General Surgery, Xi'an Children's Hospital Affiliated to Xi'an Jiaotong University, 69 Xijuyuan Lane, Lianhu District, Xi'an 710003, China.
Integr Biol (Camb). 2025 Jan 8;17. doi: 10.1093/intbio/zyaf011.
Hirschsprung's disease (HSCR) is a congenital intestinal disease characterized by the loss of enteric neural crest cells. BMI1 is demonstrated to be downregulated in HSCR tissues compared to normal intestinal tissues, but it is still unclear whether BMI1 is involved in the pathogenesis of HSCR. Here, we found that BMI1 expression was downregulated in HSCR-stenosed segments (HSCR-S) cases compared with HSCR-dilated segments (HSCR-D) or control cases. Pharmacological inhibition of BMI1 using PTC-209 significantly attenuated cell proliferation, migration, and cell cycle progression in both SH-SY5Y neuroblastoma cells and primary enteric neural crest cells (ENCCs), whereas BMI1 overexpression produced the opposite effects. BMI1 binds to the promoter region of the Wnt signaling pathway inhibitor Axin2 and suppressed its transcription by increasing H2AK119ub and reducing H3K4me3 at the Axin2 promoter, thereby hindering Wnt signaling. Moreover, overexpression of Axin2 decreased cell proliferation, migration and cell cycle progression. Treatment with HY-122816 (a Wnt signaling pathway agonist) reversed the inhibitory effects of PTC-209 on cell proliferation, migration, and cell cycle progression. Additionally, BMI1 upregulation promoted ganglion cell proliferation in Ednrb-/- mice. In conclusion: BMI1 facilitated Wnt signaling by mediating epigenetic silencing of Axin2, thereby promoting cell proliferation and migration in HSCR. Clinically, BMI1 expression was downregulated in HSCR-S cases compared with HSCR-D or control cases. Moreover, BMI1 was shown for the first time to promote cell proliferation, migration, and cell cycle progression in ENCCs. Molecular level probing revealed that BMI1 binds to the promoter region of Axin2, an inhibitor of the Wnt signaling pathway, and inhibited Axin2 transcription by increasing H2AK119ub and decreasing H3K4me3 in the Axin2 promoter, thereby hindering Wnt signaling. This study revealed that the BMI1/Axin2/Wnt axis may play an important role in the pathogenesis of HSCR.
先天性巨结肠症（HSCR）是一种以肠神经嵴细胞缺失为特征的先天性肠道疾病。与正常肠道组织相比，BMI1在HSCR组织中表达下调，但BMI1是否参与HSCR的发病机制仍不清楚。在此，我们发现与HSCR扩张段（HSCR-D）或对照病例相比，BMI1在HSCR狭窄段（HSCR-S）病例中表达下调。使用PTC-209对BMI1进行药理学抑制可显著减弱SH-SY5Y神经母细胞瘤细胞和原代肠神经嵴细胞（ENCCs）中的细胞增殖、迁移和细胞周期进程，而BMI1过表达则产生相反的效果。BMI1与Wnt信号通路抑制剂Axin2的启动子区域结合，并通过增加Axin2启动子处的H2AK119ub和减少H3K4me3来抑制其转录，从而阻碍Wnt信号传导。此外，Axin2的过表达降低了细胞增殖、迁移和细胞周期进程。用HY-122816（一种Wnt信号通路激动剂）处理可逆转PTC-209对细胞增殖、迁移和细胞周期进程的抑制作用。此外，BMI1上调促进了Ednrb-/-小鼠中的神经节细胞增殖。总之：BMI1通过介导Axin2的表观遗传沉默促进Wnt信号传导，从而促进HSCR中的细胞增殖和迁移。临床上，与HSCR-D或对照病例相比，BMI1在HSCR-S病例中表达下调。此外，首次证明BMI1可促进ENCCs中的细胞增殖、迁移和细胞周期进程。分子水平探究表明，BMI1与Wnt信号通路抑制剂Axin2的启动子区域结合，并通过增加Axin2启动子处的H2AK119ub和减少H3K4me3来抑制Axin2转录，从而阻碍Wnt信号传导。本研究表明，BMI1/Axin2/Wnt轴可能在HSCR的发病机制中起重要作用。
