Shang Lei, Wei Minjie
School of Pharmacy, China Medical University, Shenyang, China.
Shenyang Medical College, Shenyang, China.
Front Oncol. 2019 Apr 26;9:306. doi: 10.3389/fonc.2019.00306. eCollection 2019.
The protein lysine methyltransferase SMYD2 has recently emerged as a new enzyme modulate gene transcription or signaling pathways, and involved into tumor progression. However, the role of SMYD2 in drug resistant is still not known. Here, we found that inhibition of SMYD2 by specific inhibitor could enhance the cell sensitivity to cisplatin (CDDP), but not paclitaxel, NVB, and VCR in non-small cell lung cancer (NSCLC). Further study showed that SMYD2 and its substrates were overexpressed in NSCLC resistant cells, and the inhibition of SMYD2 or knockdown by specific siRNA could reverse the cell resistance to cisplatin treatment in NSCLC/CDDP cells. In addition, our data indicated that the inhibition or knockdown SMYD2 inhibit tumor sphere formation and reduce cell migration in NSCLC/CDDP cells, but not in NSCLC parental cells. Mechanistically, inhibition of SMYD2 could enhance p53 pathway activity and induce cell apoptosis through regulating its target genes, including p21, GADD45, and Bax. On the contrary, the sensitivity of cells to cisplatin was decreased after knockdown p53 or in p53 deletion NSCLC cells. The synergistically action was further confirmed by experiments. Taken together, our results demonstrate SMYD2 is involved into cisplatin resistance through regulating p53 pathway, and might become a promising therapeutic target for cisplatin resistance in NSCLC.
蛋白质赖氨酸甲基转移酶SMYD2最近作为一种调节基因转录或信号通路的新酶出现，并参与肿瘤进展。然而，SMYD2在耐药性中的作用仍不清楚。在此，我们发现用特异性抑制剂抑制SMYD2可增强非小细胞肺癌（NSCLC）细胞对顺铂（CDDP）的敏感性，但对紫杉醇、长春瑞滨和长春新碱不敏感。进一步研究表明，SMYD2及其底物在NSCLC耐药细胞中过表达，抑制SMYD2或用特异性siRNA敲低可逆转NSCLC/CDDP细胞对顺铂治疗的耐药性。此外，我们的数据表明，抑制或敲低SMYD2可抑制NSCLC/CDDP细胞中的肿瘤球形成并减少细胞迁移，但对NSCLC亲本细胞无此作用。机制上，抑制SMYD2可通过调节其靶基因（包括p21、GADD45和Bax）增强p53通路活性并诱导细胞凋亡。相反，敲低p53后或在p53缺失的NSCLC细胞中，细胞对顺铂的敏感性降低。实验进一步证实了协同作用。综上所述，我们的结果表明SMYD2通过调节p53通路参与顺铂耐药，可能成为NSCLC顺铂耐药的一个有前景的治疗靶点。
