POU6F1 cooperates with RORA to suppress the proliferation of lung adenocarcinoma by downregulating HIF1A signaling pathway

Abstract Lung adenocarcinoma (LUAD) represents the most frequently diagnosed histological subtype of non-small cell lung cancer with the highest mortality worldwide. Transcriptional dysregulation is a hallmark of nearly all kinds of cancers. In the study, we identified that the POU domain, class 6, transcription factor 1 (POU6F1), a member of the POU family of transcription factors, was closely associated with tumor stage and death in LUAD. We revealed that POU6F1 was downregulated in LUAD tissues and downregulated POU6F1 was predictive of an unfavorable prognosis in LUAD patients. In vitro assays, including CCK8, soft agar, transwell, clone formation, wound-healing assay, and nude mouse xenograft model all revealed that POU6F1 inhibited the growth and invasion of LUAD cells. Mechanistically, POU6F1 bound and stabilized retinoid-related orphan receptor alpha (RORA) to exert the transcriptional inhibition of hypoxia-inducible factor 1-alpha (HIF1A) and alter the expression of HIF1A signaling pathway-associated genes, including ENO1, PDK1, and PRKCB, thereby leading to the suppression of LUAD cells. Collectively, these results demonstrated the suppressive role of POU6F1/RORA in the progression of LUAD and may potentially be used as a target for the treatment of LUAD.