RESUMEN
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.
RESUMEN
Nur77 belongs to the NR4A subfamily of orphan nuclear hormone receptors. It has been shown to play important roles in metabolism, cancer progression, cellular differentiation, and the regulation of immune process. However, there has yet to be research reporting on the role of Nur77 in allergic inflammations such as anaphylaxis. This study aimed to identify molecules that could mediate allergic inflammations. To this end, we performed RNA sequencing analysis employing bone marrow-derived mast cells (BMMCs). Antigen (DNP-HSA) stimulation increased the expression levels of transcription factors such as Nr4a3 (NOR1), Nr4a1 (Nur77), and Nr4a2 (Nurr1). We focused our study on Nur77. Antigen stimulation increased the expression of Nur77 in a time- and dose-dependent manner in rat basophilic leukemia cells (RBL2H3). The downregulation of Nur77 prevented both antigen-induced increase in ß-hexosaminidase activity as well as hallmarks of allergic reactions such as HDAC3, COX2, and MCP1 in RBL2H3 cells. Nur77 was necessary for both passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA). TargetScan analysis predicted that miR-21a would be a negative regulator of Nur77. miR-21a mimic negatively regulated PCA and PSA by inhibiting the hallmarks of allergic reactions. ChIP assays showed that c-JUN could bind to the promoter sequences of Nur77. Antigen stimulation increased the expression of c-JUN in RBL2H3 cells. Altogether, our findings demonstrate the regulatory role played by Nur77-miR-21a loop in allergic inflammations such as anaphylaxis, making this the first report to present the role played by Nur77 in an allergic inflammation. Our results suggest that Nur77 and miR-21 might serve as targets for developing anti-allergy drugs.