RP11‐367G18.1 V2 enhances clear cell renal cell carcinoma progression via induction of epithelial–mesenchymal transition

• Published in: Cancer medicine (Malden, MA) Vol. 12; no. 8; pp. 9788 - 9801
• Main Authors: Shao, I‐Hung, Peng, Pei‐Hua, Wu, Heng‐Hsiung, Chen, Ji‐Lin, Lai, Joseph Chieh‐Yu, Chang, Jeng‐Shou, Wu, Han‐Tsang, Wu, Kou‐Juey, Pang, See‐Tong, Hsu, Kai‐Wen
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-04-2023; John Wiley and Sons Inc; Wiley
• Subjects: Acetylation; Animal models; Animals; Biomarkers; Carcinoma - genetics; Carcinoma, Renal Cell - pathology; Cell culture; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; Chromatin; clear cell renal cell carcinoma; Clear cell-type renal cell carcinoma; Epigenetics; Epithelial-Mesenchymal Transition - genetics; epithelial–mesenchymal transition; Gene expression; Gene Expression Regulation, Neoplastic; Growth models; H4K16Ac; Histone acetyltransferase; Humans; Hypoxia; Hypoxia - genetics; Hypoxia-inducible factor 1a; Kidney cancer; Kidney Neoplasms - pathology; lncRNA RP11‐367G18.1; Medical prognosis; Metastases; Metastasis; Mice; Microenvironments; Non-coding RNA; Parenchyma; Phenotypes; Plasmids; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Therapeutic targets; Transcription factors; Tumor Microenvironment; Tumorigenesis; Tumorigenicity; Tumors; hypoxia; H4K16Ac; epithelial-mesenchymal transition; clear cell renal cell carcinoma; lncRNA RP11-367G18.1
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.5723

Purpose
Metastasis 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 lncRNA RP11‐367G18.1 induced by hypoxia, that was overexpressed in ccRCC tissues.
Methods
A total of 216 specimens, including 149 ccRCC tumor samples and 67 related normal kidney parenchyma tissue samples, were collected. To investigate the biological fucntions of RP11.367G18.1 in ccRCC, migration, invasion, soft agar colony formation, xenograft tumorigenicity assays, and tail vein and orthotopic metastatic mouse models were performed. The relationship between RP11‐367G18.1 and downstream signaling was analyzed utilizing reporter assay, RNA pull‐down, chromatin immunopreciptation, and chromatin isolation by RNA purification assays.
Results
Hypoxic conditions and overexpression of HIF‐1α increased the level of RP11‐367G18.1. RP11‐367G18.1 induced EMT and enhanced cell migration and invasion through variant 2. Inhibition of RP11‐367G18.1 variant 2 reversed hypoxia‐induced EMT phenotypes. An in vivo study revealed that RP11‐367G18.1 variant 2 was required for hypoxia‐induced tumor growth and metastasis in ccRCC. Mechanistically, RP11‐367G18.1 variant 2 interacted with p300 histone acetyltransferase to regulate lysine 16 acetylation on histone 4 (H4K16Ac), thus contributing to hypoxia‐regulated gene expression. Clinically, RP11‐367G18.1 variant 2 was upregulated in ccRCC tissues, particularly metastatic ccRCC tissues, and it is linked to poor overall survival.
Conclusion
These findings demonstrate the prognostic value and EMT‐promoting role of RP11‐367G18.1 and indicate that this lncRNA may provide a therapeutic target for ccRCC.
Hypoxia upregulated lncRNA RP11‐367G18.1 variant 2 which was associated with p300‐mediated chromatin modifying complex to activate H4K16Ac marks. RP11‐367G18.1 variant 2 increased the levels of H4K16Ac on the promoter of hypoxia‐regulated genes leading to EMT and tumor metastasis.