Epigenetic silencing of miR-137 induces drug resistance and chromosomal instability by targeting AURKA in multiple myeloma

Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Aberrant microRNAs (miRNAs) expression has been shown to be involved in the pathogenesis of MM. In this study, we further demonstrated that miR-137 was significantly downregulated in MM and negatively correlated with clinical prognosis. Moreover, we described the epigenetic regulation of miR-137 and its association with progression-free survival in MM patients. Furthermore, overexpression of miR-137 in MM cell line (miR-137 OE) increased its sensitivity to bortezomib and eprirubicin in vitro. Also, some high-risk genetic abnormalities in MM, including deletion of chromosome 1p22.2, 14q or 17p13, and gain of chromosome 1p22.2 were detected in NCI-H929 empty vector (NCI-H929 EV) treated cells but not in the NCI-H929 miR-137 overexpression (NCI-H929 miR-137 OE) cells. Luciferase reporter assays demonstrated that miR-137 targeted AURKA. Ectopic expression of miR-137 strongly reduced the expression of AURKA and p-ATM/Chk2 in MM cells, and increased the expression of p53, and p21. Importantly, miR-137 overexpression together with bortezomib treatment significantly inhibited tumor growth in MM xenograft model. Taken together, this study demonstrates that miR-137 is epigenetically silenced in MM, and overexpression of miR-137 could reduce drug resistance and overcome chromosomal instability of the MM cells via affecting the apoptosis and DNA damage pathways.

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ATM/ATR Autophagy