Xue Wenhua, Shen Zhibo, Li Lifeng, Zheng Yuanyuan, Yan Dan, Kan Quancheng, Zhao Jie
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
Mol Ther Nucleic Acids. 2020 Dec 10;23:592-602. doi: 10.1016/j.omtn.2020.12.007. eCollection 2021 Mar 5.
The nuclear receptor-binding SET domain (NSD) protein family encoding histone lysine methyltransferases is involved in cancer progression. However, the role of NSDs in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we examined the expression of NSDs in cisplatin-resistant and parental ESCC cells and revealed the upregulation of NSD2 in cisplatin-resistant cells. Ectopic expression of NSD2 increased cisplatin resistance and attenuated cisplatin-induced apoptosis. Colony formation assay indicated that NSD2 overexpression enhanced long-term survival of ESCC cells after treatment with cisplatin. In contrast, knockdown of NSD2 inhibited ESCC cell proliferation and sensitized ESCC cells to cisplatin. Depletion of NSD2 augmented the cytotoxic effect of cisplatin on EC109 xenograft tumors. NSD2 stimulated long non-coding RNA MACC1-AS1 in ESCC cells. Knockdown of MACC1-AS1 impaired NSD2-induced cisplatin resistance. Moreover, MACC1-AS1 overexpression promoted ESCC cell proliferation and cisplatin resistance. Clinically, MACC1-AS1 was upregulated in ESCC relative to adjacent noncancerous tissues. High MACC1-AS1 levels were significantly associated with reduced overall survival of ESCC patients. There was a positive correlation between MACC1-AS1 and NSD2 expression in ESCC specimens. Taken together, MACC1-AS1 induced by NSD2 mediates resistance to cisplatin in ESCC and may represent a novel target to improve cisplatin-based chemotherapy.
编码组蛋白赖氨酸甲基转移酶的核受体结合SET结构域（NSD）蛋白家族参与癌症进展。然而，NSD在食管鳞状细胞癌（ESCC）中的作用仍不清楚。在此，我们检测了NSD在顺铂耐药和亲本ESCC细胞中的表达，并发现顺铂耐药细胞中NSD2上调。NSD2的异位表达增加了顺铂耐药性并减弱了顺铂诱导的细胞凋亡。集落形成试验表明，NSD2过表达增强了ESCC细胞在顺铂处理后的长期存活能力。相反，敲低NSD2抑制了ESCC细胞增殖并使ESCC细胞对顺铂敏感。去除NSD2增强了顺铂对EC109异种移植瘤的细胞毒性作用。NSD2在ESCC细胞中刺激长链非编码RNA MACC1-AS1。敲低MACC1-AS1削弱了NSD2诱导的顺铂耐药性。此外，MACC1-AS1过表达促进了ESCC细胞增殖和顺铂耐药性。临床上，相对于相邻的非癌组织，ESCC中MACC1-AS1上调。高MACC1-AS1水平与ESCC患者总生存期降低显著相关。ESCC标本中MACC1-AS1与NSD2表达呈正相关。综上所述，NSD2诱导的MACC1-AS1介导了ESCC对顺铂的耐药性，可能代表了一个改善基于顺铂化疗的新靶点。
