TY - JOUR AB - SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a histone H3K9 methyltransferase that stimulates cell proliferation by methylating AKT, which contributes to drug resistance in multiple myeloma (MM). Lenalidomide is an immunomodulatory agent widely used in the treatment of MM. However, lenalidomide resistance occurs in patients with MM. Currently, the role of SETDB1 in lenalidomide resistance in MM remains unclear. Thus, the present study aimed to explore the functional association between SETDB1 and lenalidomide resistance in MM. The analysis of GEO datasets revealed that SETDB1 was upregulated in lenalidomide‑resistant MM cells and that its expression was associated with poor prognosis of patients with MM. Apoptosis analysis revealed that overexpression of SETDB1 in MM cells significantly decreased apoptosis, while knockdown of SETDB1 increased apoptosis. Furthermore, the IC50 value of lenalidomide in MM cells increased following SETDB1 overexpression and decreased following SETDB1 silencing. Additionally, SETDB1 mediated epithelial‑mesenchymal transition (EMT) and activated the PI3K/AKT pathway. Mechanistic analysis revealed that inhibition of PI3K/AKT signaling in MM cells increased apoptosis, sensitized the cells to lenalidomide and inhibited EMT, whereas SETDB1 overexpression inhibited the effects of PI3K/AKT cascade inhibition. In conclusion, the findings of the present study indicated that SETDB1 promoted lenalidomide resistance in MM cells by promoting EMT and the PI3K/AKT signaling pathway. Thus, SETDB1 may be a potential therapeutic target for MM. AD - Department of Hematology, The Second People's Hospital of Taizhou, Medical College of Yangzhou University, Jiangyan, Taizhou, Jiangsu 225500, P.R. China Department of Gastroenterology, The Second People's Hospital of Taizhou, Medical College of Yangzhou University, Jiangyan, Taizhou, Jiangsu 225500, P.R. China AU - Qian,Xiaoli AU - Yang,Yang AU - Deng,Yingfen AU - Liu,Yali AU - Zhou,Yuwen AU - Han,Fang AU - Xu,Yue AU - Yuan,Hongjian DA - 2023/06/01 DO - 10.3892/etm.2023.11973 IS - 6 JO - Exp Ther Med KW - SET domain bifurcated histone lysine methyltransferase 1 epithelial‑mesenchymal transition PI3K/AKT signaling pathway lenalidomide drug‑resistance multiple myeloma PY - 2023 SN - 1792-0981 1792-1015 SP - 274 ST - SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation T2 - Experimental and Therapeutic Medicine TI - SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation UR - https://doi.org/10.3892/etm.2023.11973 VL - 25 ER -