HOTAIR contributes to chemoresistance by activating NF-κB signaling in small-cell lung cancer.

ABSTRACT

Our previous study showed that lncRNA HOTAIR affects the chemoresistance of SCLC by regulating HOXA1 methylation. However, the downstream regulatory mechanism remains unknown. The article aimed to further explore the potential downstream mechanism. In this study, we demonstrate that the knockdown of HOTAIR inhibits the NF-κB pathway in SCLC cells. The overexpression of HOXA1, the downstream gene of HOTAIR, also suppresses the NF-κB pathway, but the downregulation of HOXA1 shows the opposite results. Notably, the knockdown of HOXA1 in HOTAIR downregulated cells can rescue the inhibition of the NF-κB pathway mediated by HOTAIR downregulation. Meanwhile, we found that the NF-κB pathway is activated in multidrug-resistant SCLC cells (H69AR, H446AR) compared with the parental cells (H69, H446). The inhibition of the NF-κB pathway with celastrol increases cell sensitivity to anticancer drugs, cell apoptosis, and cell cycle arrest. Collectively, these results revealed that the NF-κB pathway may be involved in the chemoresistance of SCLC caused by HOTAIR methylating HOXA1.