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

Hamilton, Michael J; Young, Matthew; Jang, Kay; Sauer, Silvia; Neang, Vanessa E; King, Alexia T; Girke, Thomas; Martinez, Ernest

Hamilton, Michael J; Young, Matthew; Jang, Kay; Sauer, Silvia; Neang, Vanessa E; King, Alexia T; Girke, Thomas; Martinez, Ernest.

Afiliación

Hamilton MJ; Department of Biochemistry, University of California, Riverside, CA, USA.
Young M; Department of Biochemistry, University of California, Riverside, CA, USA.
Jang K; Department of Biochemistry, University of California, Riverside, CA, USA.
Sauer S; Department of Biochemistry, University of California, Riverside, CA, USA.
Neang VE; Department of Biochemistry, University of California, Riverside, CA, USA.
King AT; Department of Biochemistry, University of California, Riverside, CA, USA.
Girke T; Department of Botany and Plant Sciences, University of California, Riverside, CA, USA.
Martinez E; Department of Biochemistry, University of California, Riverside, CA, USA. Electronic address: ernest.martinez@ucr.edu.

Cancer Lett ; 472: 50-58, 2020 03 01.

Article en En | MEDLINE | ID: mdl-31862408

RESUMEN

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.

Asunto(s)

Proteína 4 Similar a la Angiopoyetina/genética; Carcinoma de Células Renales/genética; Subunidad alfa del Factor 1 Inducible por Hipoxia/genética; MicroARNs/genética; Apoptosis/genética; Carcinoma de Células Renales/patología; Diferenciación Celular/genética; Línea Celular Tumoral; Linaje de la Célula/genética; Proliferación Celular/genética; Regulación Neoplásica de la Expresión Génica/genética; Humanos; Riñón/crecimiento & desarrollo; Riñón/patología; Isoformas de Proteínas/genética; Transducción de Señal/genética; Hipoxia Tumoral/genética

Palabras clave

Cell differentiation; Hypoxia-Inducible Factor 1α (HIF1α); Kidney lineage; Long non-coding RNA; ccRCC

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / MicroARNs / Subunidad alfa del Factor 1 Inducible por Hipoxia / Proteína 4 Similar a la Angiopoyetina Límite: Humans Idioma: En Revista: Cancer Lett Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda

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