HDAC9 and miR-512 Regulate CAGE-Promoted Anti-Cancer Drug Resistance and Cellular Proliferation
Minjeong Yeon | Nayeon Kwon | Jaewhoon Jeoung | Dooil Jeoung
Histone deacetylase 9 (HDAC9) is known to be upregulated in various cancers. Cancer-associated antigens (<i>CAGEs</i>) 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. AGS<sup>R</sup> 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 AGS<sup>R</sup> cells. CAGEs directly regulated the expression of HDAC9. Rapamycin, an inducer of autophagy, increased HDAC9 expression in AGS, whereas chloroquine decreased HDAC9 expression in AGS<sup>R</sup> cells. The downregulation of <i>HDAC9</i> decreased the autophagic flux, invasion, migration, and tumor spheroid formation potential in AGS<sup>R</sup> 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 AGS<sup>R</sup> cells. The culture medium of AGS<sup>R</sup> increased the expression of HDAC9 and autophagic flux in AGS. A human recombinant CAGE protein increased HDAC9 expression in AGS cells. AGS<sup>R</sup> 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.
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