HOTAIR Promotes Prostate Cancer Progression by facilitating CDK9-Pol II Association and Transcriptional Elongation.

Abstract

Previous research has predominantly focused on the regulatory role of lncRNA HOTAIR in gene silencing by interacting with the Polycomb repressive complex 2 (PRC2), but its direct role as a transcriptional activator remains less well characterized. Here, our study reveals a novel regulatory mechanism of HOTAIR, which facilitates prostate cancer (PCa) progression by enhancing transcription elongation. Integrating ChIRP-seq, RNA-seq, and ChIP-seq, we found that HOTAIR co-localizes with AR and facilitates the interaction between CDK9 and Pol II. This function requires the 1-442 nt region and intact RNA, as deletion or RNase treatment disrupts the interaction. Re-expression of full-length HOTAIR, but not the deletion mutant, restores nascent transcription of target genes; conversely, CDK9 inhibition suppresses this elongation effect. We identified MMP14 and TNFAIP2 as functional downstream targets; ectopic expression of either rescues colony formation and invasive migration upon HOTAIR depletion. HOTAIR knockdown reduced Ser2P and Ser5P signals at target loci, yet RNA pull-down showed no direct binding to Pol II Ser5P, implying that any effect on initiation is indirect. This elongation activity operates in both AR-positive and AR-negative cells, with AR acting as a context-specific recruiter. Collectively, these findings support a model in which HOTAIR functions as an elongation activator and suggest potential therapeutic targets in prostate cancer.