AbstractPurposeMetastasis is the end stage of renal cell carcinoma (RCC), and clear cell renal cell carcinoma (ccRCC) is the most common malignant subtype. The hypoxic microenvironment is a common feature in ccRCC and plays an essential role in the regulation of epithelial–mesenchymal transition (EMT). Accumulating evidence manifests that long non‐coding RNAs (lncRNAs) participate in RCC tumorigenesis and regulate hypoxia‐induced EMT. Here, we identified a lncRNARP11‐367G18.1induced by hypoxia, that was overexpressed in ccRCC tissues.MethodsA total of 216 specimens, including 149 ccRCC tumor samples and 67 related normal kidney parenchyma tissue samples, were collected. To investigate the biological fucntions ofRP11.367G18.1in ccRCC, migration, invasion, soft agar colony formation, xenograft tumorigenicity assays, and tail vein and orthotopic metastatic mouse models were performed. The relationship betweenRP11‐367G18.1and downstream signaling was analyzed utilizing reporter assay, RNA pull‐down, chromatin immunopreciptation, and chromatin isolation by RNA purification assays.ResultsHypoxic conditions and overexpression of HIF‐1α increased the level ofRP11‐367G18.1.RP11‐367G18.1induced EMT and enhanced cell migration and invasion through variant 2. Inhibition ofRP11‐367G18.1variant 2 reversed hypoxia‐induced EMT phenotypes. An in vivo study revealed thatRP11‐367G18.1variant 2 was required for hypoxia‐induced tumor growth and metastasis in ccRCC. Mechanistically,RP11‐367G18.1variant 2 interacted with p300 histone acetyltransferase to regulate lysine 16 acetylation on histone 4 (H4K16Ac), thus contributing to hypoxia‐regulated gene expression. Clinically,RP11‐367G18.1variant 2 was upregulated in ccRCC tissues, particularly metastatic ccRCC tissues, and it is linked to poor overall survival.ConclusionThese findings demonstrate the prognostic value and EMT‐promoting role ofRP11‐367G18.1and indicate that this lncRNA may provide a therapeutic target for ccRCC.