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
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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.
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ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2019.12.022