MBD2 regulates the progression and chemoresistance of cholangiocarcinoma through interaction with WDR5
Background: Cholangiocarcinoma (CCA) is a high malignancy, rapid progression tumor of bile duct. Due to its chemoresistance, it always has an extremely poor prognosis. Therefore, it is still need to detailed elucidation the mechanisms of chemoresistance and find the therapeutic targets. Methods: We analysis the expression of MBD2 in CCA and normal bile duct tissues through public database and immunohistochemical (IHC). The role of MBD2 in CCA cells' proliferation, migration, chemoresistance ability was validated through CCK-8, plate clone assay, wound healing assay, xenograft mice models. Besides, we construct a primary CCA mice model to further confirm the effect of MBD2. RNA-seq, co-IP-MS were used to find the mechanisms of MBD2 leading to chemoresistance. Results: MBD2 is up-regulated in CCA. It could promote the proliferation, migration and chemoresistance of CCA cells. Mechanistically, MBD2 could directly interact with WDR5, and binding to the promoter of ABCB1, then promote the tri-methylation of H3K4 in this region through KMT2A, active the expression of ABCB1. Knocking down of WDR5 or KMT2A could block the transcriptional activation of ABCB1 by MBD2. MM-102 is a molecular inhibitor that targets the interaction of WDR5 with KMT2A. MM-102 could inhibit the expression of ABCB1 in CCA cells, and decrease the chemoresistance of CCA to cisplatin. Conclusion: MBD2 promote the progress and chemoresistance of CCA through interact with WDR5. MM-102 could effectively block this procedure and enhance the sensitivity to cisplatin of CCA. Overall design: To investigate the factors regulated by MBD2 in CCA cells, RNA-seq analysis of knockdown of MBD2 and negative control TFK1 cells was performed.