KDM1A promotes thyroid cancer progression and maintains stemness through the Wnt/β-catenin signaling pathway.
KDM1A promotes thyroid cancer progression and maintains stemness through the Wnt/β-catenin signaling pathway.
复制标题
作者：
Zhang W;Ruan X;Li Y;Zhi J;Hu L;Hou X;Shi X;Wang X;Wang J;Ma W;Gu P;Zheng X;Gao M
背景：肿瘤干细胞（CSCs）具有高度致瘤性、耐化疗性、维持肿瘤生长，并与肿瘤复发有关。先前的研究表明，赖氨酸特异性组蛋白去甲基化酶1A（KDM 1A）在几种人类恶性肿瘤和CSC中高度表达。然而，KDM 1A在CSC中的作用以及KDM 1A抑制剂用于治疗晚期甲状腺癌的治疗潜力知之甚少。研究方法：首先，KDM 1A被确定为一个重要的表观遗传修饰剂，通过一个迷你组蛋白甲基化修饰剂筛选，并在甲状腺癌组织和细胞系中证实，维持甲状腺癌的干性。进行RNA测序以发现KDM 1A的下游基因。通过ChIP、IP和双荧光素酶报告基因测定、功能获得和丧失测定进一步研究了潜在机制。结果：在这里，我们报告了KDM 1A通过Wnt/β-catenin途径调节甲状腺癌的干性并促进甲状腺癌的进展。在机制上，KDM 1A通过使APC 2启动子区的H3 K4 me 1/2和非组蛋白底物HIF-1α去甲基化，下调经典Wnt途径的两种拮抗剂APC 2和DKK 1，导致APC 2转录抑制和HIF-1α/microRNA-146 a/DKK 1轴激活。重要的是，我们还证明了GSK-LSD 1，一种高度选择性的KDM 1A抑制剂，可显著抑制甲状腺癌的进展，并增强甲状腺癌对化疗的敏感性。结论：KDM 1A在甲状腺癌的发生、发展过程中起重要作用，为甲状腺癌的治疗提供了新的策略。
Background: Cancer stem cells (CSCs) are highly tumorigenic, chemotherapy-resistant, tumor growth-sustaining, and are implicated in tumor recurrence. Previous studies have shown that lysine-specific histone demethylase 1A (KDM1A) is highly expressed in several human malignancies and CSCs. However, the role of KDM1A in CSCs and the therapeutic potential of KDM1A inhibitors for the treatment of the advanced thyroid cancer are poorly understood. Methods: Firstly, KDM1A was identified as an important epigenetic modifier that maintained the stemness of thyroid cancer through a mini histone methylation modifier screen and confirmed in thyroid cancer tissues and cell lines. RNA sequence was performed to discover the downstream genes of KDM1A. The underlying mechanisms were further investigated by ChIP, IP and dual luciferase reporter assays, gain and loss of function assays. Results: Here we report that KDM1A regulates the stemness of thyroid cancer and promotes thyroid cancer progression via the Wnt/β-catenin pathway. Mechanistically, KDM1A down-regulates two antagonists of the canonical Wnt pathway, APC2 and DKK1, by demethylating H3K4me1/2 of the APC2 promoter region and the nonhistone substrate HIF-1α, resulting in the inhibition of APC2 transcription and the activation of the HIF-1α/microRNA-146a/DKK1 axis. Importantly, we also demonstrate that GSK-LSD1, a highly selective inhibitor of KDM1A, significantly inhibits thyroid cancer progression and enhances the sensitivity of thyroid cancer to chemotherapy. Conclusions: KDM1A plays an important role in thyroid cancer progression and maintains stemness, our study provides a new strategy for the therapy of advanced thyroid cancer.