PDF(Pubmed)
Abstract：
Histone deacetylase 9 (HDAC9) is known to be upregulated in various cancers. Cancer-associated antigens (CAGEs) are cancer/testis antigens that play an important role in anti-cancer drug resistance. This study aimed to investigate the relationship between CAGEs and HDAC9 in relation to anti-cancer drug resistance. AGSR cells with an anti-cancer drug-resistant phenotype showed higher levels of CAGEs and HDAC9 than normal AGS cells. CAGEs regulated the expression of HDAC9 in AGS and AGSR cells. CAGEs directly regulated the expression of HDAC9. Rapamycin, an inducer of autophagy, increased HDAC9 expression in AGS, whereas chloroquine decreased HDAC9 expression in AGSR cells. The downregulation of HDAC9 decreased the autophagic flux, invasion, migration, and tumor spheroid formation potential in AGSR cells. The TargetScan analysis predicted that miR-512 was a negative regulator of HDAC9. An miR-512 mimic decreased expression levels of CAGEs and HDAC9. The miR-512 mimic also decreased the autophagic flux, invasion, migration, and tumor spheroid forming potential of AGSR cells. The culture medium of AGSR increased the expression of HDAC9 and autophagic flux in AGS. A human recombinant CAGE protein increased HDAC9 expression in AGS cells. AGSR cells displayed higher tumorigenic potential than AGS cells. Altogether, our results show that CAGE-HDAC9-miR-512 can regulate anti-cancer drug resistance, cellular proliferation, and autophagic flux. Our results can contribute to the understanding of the molecular roles of HDAC9 in anti-cancer drug resistance.
摘要：
已知组蛋白脱乙酰酶9(HDAC9)在各种癌症中上调。癌症相关抗原（CAGE）是在抗癌药物耐药性中起重要作用的癌症/睾丸抗原。本研究旨在探讨CAGE和HDAC9与抗癌药物耐药的关系。具有抗癌药物抗性表型的AGSR细胞显示比正常AGS细胞更高水平的CAGE和HDAC9。CAGEs调控AGS和AGSR细胞中HDAC9的表达。CAGEs直接调控HDAC9的表达。雷帕霉素,自噬的诱导剂,AGS中HDAC9表达增加，而氯喹降低AGSR细胞中HDAC9的表达。HDAC9的下调降低了自噬通量，入侵,迁移,和AGSR细胞中的肿瘤球状体形成潜力。TargetScan分析预测miR-512是HDAC9的负调节因子。miR-512模拟物降低CAGE和HDAC9的表达水平。miR-512模拟物也降低了自噬通量，入侵,迁移,和AGSR细胞的肿瘤球体形成潜力。AGSR的培养基增加了AGS中HDAC9的表达和自噬通量。人重组CAGE蛋白增加AGS细胞中HDAC9的表达。AGSR细胞显示出比AGS细胞更高的致瘤潜能。总之,我们的结果表明，CAGE-HDAC9-miR-512可以调节抗癌药物的耐药性，细胞增殖，和自噬通量。我们的研究结果有助于理解HDAC9在抗癌药物耐药性中的分子作用。
