HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway

HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) is a conserved long non-coding RNA (lncRNA) involved in myeloid and neural differentiation that is deregulated in acute myeloid leukemia and other cancers. Previous studies focused on the nuclear unspliced HOTAIRM1 transcript, however cyto...

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Published in:	Cancer letters Vol. 472; pp. 50 - 58
Main Authors:	Hamilton, Michael J., Young, Matthew, Jang, Kay, Sauer, Silvia, Neang, Vanessa E., King, Alexia T., Girke, Thomas, Martinez, Ernest
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier B.V 01-03-2020 Elsevier Limited
Subjects:	Acute myeloid leukemia Alternative splicing Angiogenesis Angiopoietin-like 4 Protein - genetics Antisense RNA Apoptosis - genetics Archives & records Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - pathology ccRCC Cell culture Cell differentiation Cell Differentiation - genetics Cell Line, Tumor Cell Lineage - genetics Cell Proliferation - genetics Clear cell-type renal cell carcinoma Embryo cells Gene expression Gene Expression Regulation, Neoplastic - genetics Genomes Genomics Humans Hypoxia Hypoxia-inducible factor 1 Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-inducible factor 1a Hypoxia-Inducible Factor 1α (HIF1α) Kidney - growth & development Kidney - pathology Kidney cancer Kidney lineage Kidneys Leukemia Long non-coding RNA MicroRNAs - genetics Myeloid leukemia Non-coding RNA Post-transcription Protein Isoforms - genetics Signal Transduction - genetics Software Stem cells Tumor Hypoxia - genetics Tumors Grand Island United States > US ccRCC Kidney lineage Cell differentiation Hypoxia-Inducible Factor 1α (HIF1α) Long non-coding RNA
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Summary:	HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) is a conserved long non-coding RNA (lncRNA) involved in myeloid and neural differentiation that is deregulated in acute myeloid leukemia and other cancers. Previous studies focused on the nuclear unspliced HOTAIRM1 transcript, however cytoplasmic splice variants exist whose roles have remained unknown. Here, we report novel functions of HOTAIRM1 in the kidney. HOTAIRM1 transcripts are induced during renal lineage differentiation of embryonic stem cells and required for expression of specific renal differentiation genes. We show that the major HOTAIRM1 transcript in differentiated cells is the spliced cytoplasmic HM1-3 isoform and that HM1-3 is downregulated in >90% of clear cell renal cell carcinomas (ccRCCs). Knockdown of HM1-3 in renal cells deregulates hypoxia-responsive and angiogenic genes, including ANGPTL4. Furthermore, HOTAIRM1 transcripts are downregulated by hypoxia-mimetic stress and knockdown of the cytoplasmic HM1-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1α (HIF1α) protein, a key activator of ANGPTL4. Our results demonstrate the pervasive downregulation of the specific HOTAIRM1 cytoplasmic isoform HM1-3 in ccRCC and suggest possible roles of HOTAIRM1 in kidney differentiation and suppression of HIF1-dependent angiogenic pathways. •New role of HOTAIRM1 in the kidney.•Spliced cytoplasmic isoform of HOTAIRM1 is downregulated in ccRCC.•Expression of HOTAIRM1 is associated with renal lineage differentiation.•HOTAIRM1 expression is inhibited by hypoxic stress signaling.•HOTAIRM1 downregulates Hypoxia-Inducible Factor 1α.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0304-3835 1872-7980
DOI:	10.1016/j.canlet.2019.12.022