MBD2 通过与 WDR5 的相互作用调控胆管癌的进展和化疗耐药性。

MBD2 regulates the progression and chemoresistance of cholangiocarcinoma through interaction with WDR5.

机构信息

Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China.

Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.

出版信息

J Exp Clin Cancer Res. 2024 Sep 30;43(1):272. doi: 10.1186/s13046-024-03188-4.

DOI:10.1186/s13046-024-03188-4

PMID:39350229

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11440836/

Abstract

BACKGROUND

Cholangiocarcinoma (CCA) is a highly malignant, rapidly progressing tumor of the bile duct. Owing to its chemoresistance, it always has an extremely poor prognosis. Therefore, detailed elucidation of the mechanisms of chemoresistance and identification of therapeutic targets are still needed.

METHODS

We analyzed the expression of MBD2 (Methyl-CpG-binding domain 2) in CCA and normal bile duct tissues using the public database and immunohistochemistry (IHC). The roles of MBD2 in CCA cell proliferation, migration, and chemoresistance ability were validated through CCK-8, plate cloning assay, wound healing assays and xenograft mouse model. In addition, we constructed a primary CCA mouse model to further confirm the effect of MBD2. RNA-seq and co-IP-MS were used to identify the mechanisms by how MBD2 leads to chemoresistance.

RESULTS

MBD2 was upregulated in CCA. It promoted the proliferation, migration and chemoresistance of CCA cells. Mechanistically, MBD2 directly interacted with WDR5, bound to the promoter of ABCB1, promoted the trimethylation of H3K4 in this region through KMT2A, and activated the expression of ABCB1. Knocking down WDR5 or KMT2A blocked the transcriptional activation of ABCB1 by MBD2. The molecular inhibitor MM-102 targeted the interaction of WDR5 with KMT2A. MM-102 inhibited the expression of ABCB1 in CCA cells and decreased the chemoresistance of CCA to cisplatin.

CONCLUSION

MBD2 promotes the progression and chemoresistance of CCA through interactions with WDR5. MM-102 can effectively block this process and increase the sensitivity of CCA to cisplatin.

摘要

背景

胆管癌（CCA）是一种恶性程度高、进展迅速的胆管肿瘤。由于其化疗耐药性，预后极差。因此，详细阐明其耐药机制并确定治疗靶点仍然是必要的。

方法

我们通过公共数据库和免疫组织化学（IHC）分析了 MBD2（甲基-CpG 结合域 2）在 CCA 和正常胆管组织中的表达。通过 CCK-8、平板克隆实验、划痕愈合实验和异种移植小鼠模型验证了 MBD2 在 CCA 细胞增殖、迁移和化疗耐药能力中的作用。此外，我们构建了原发性 CCA 小鼠模型，以进一步证实 MBD2 的作用。RNA-seq 和 co-IP-MS 用于鉴定 MBD2 导致化疗耐药的机制。

结果

MBD2 在 CCA 中上调。它促进了 CCA 细胞的增殖、迁移和化疗耐药性。在机制上，MBD2 直接与 WDR5 相互作用，结合到 ABCB1 的启动子上，通过 KMT2A 促进该区域 H3K4 的三甲基化，并激活 ABCB1 的表达。敲低 WDR5 或 KMT2A 阻断了 MBD2 对 ABCB1 的转录激活。分子抑制剂 MM-102 靶向 WDR5 与 KMT2A 的相互作用。MM-102 抑制了 CCA 细胞中 ABCB1 的表达，并降低了 CCA 对顺铂的化疗耐药性。