The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer

Aifu Lin; Chunlai Li; Zhen Xing; Qingsong Hu; Ke Liang; Leng Han; Cheng Wang; David H. Hawke; Shouyu Wang; Yanyan Zhang; Yongkun Wei; Guolin Ma; Peter K. Park; Jianwei Zhou; Yan Zhou; Zhibin Hu; Yubin Zhou; Jeffery R. Marks; Han Liang; Mien Chie Hung; Chunru Lin; Liuqing Yang

doi:10.1038/ncb3295

The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer

Aifu Lin, Chunlai Li, Zhen Xing, Qingsong Hu, Ke Liang, Leng Han, Cheng Wang, David H. Hawke, Shouyu Wang, Yanyan Zhang, Yongkun Wei, Guolin Ma, Peter K. Park, Jianwei Zhou, Yan Zhou, Zhibin Hu, Yubin Zhou, Jeffery R. Marks, Han Liang, Mien Chie HungChunru Lin, Liuqing Yang

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Abstract

Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

Original language	English (US)
Pages (from-to)	213-224
Number of pages	12
Journal	Nature cell biology
Volume	18
Issue number	2
DOIs	https://doi.org/10.1038/ncb3295
State	Published - Jan 28 2016

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Lin, A., Li, C., Xing, Z., Hu, Q., Liang, K., Han, L., Wang, C., Hawke, D. H., Wang, S., Zhang, Y., Wei, Y., Ma, G., Park, P. K., Zhou, J., Zhou, Y., Hu, Z., Zhou, Y., Marks, J. R., Liang, H., ... Yang, L. (2016). The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nature cell biology, 18(2), 213-224. https://doi.org/10.1038/ncb3295

Lin, A, Li, C, Xing, Z, Hu, Q, Liang, K, Han, L, Wang, C, Hawke, DH, Wang, S, Zhang, Y, Wei, Y, Ma, G, Park, PK, Zhou, J, Zhou, Y, Hu, Z, Zhou, Y, Marks, JR, Liang, H, Hung, MC, Lin, C & Yang, L 2016, 'The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer', Nature cell biology, vol. 18, no. 2, pp. 213-224. https://doi.org/10.1038/ncb3295

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title = "The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer",

abstract = "Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.",

author = "Aifu Lin and Chunlai Li and Zhen Xing and Qingsong Hu and Ke Liang and Leng Han and Cheng Wang and Hawke, {David H.} and Shouyu Wang and Yanyan Zhang and Yongkun Wei and Guolin Ma and Park, {Peter K.} and Jianwei Zhou and Yan Zhou and Zhibin Hu and Yubin Zhou and Marks, {Jeffery R.} and Han Liang and Hung, {Mien Chie} and Chunru Lin and Liuqing Yang",

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AU - Lin, Aifu

AU - Li, Chunlai

AU - Xing, Zhen

AU - Hu, Qingsong

AU - Liang, Ke

AU - Han, Leng

AU - Wang, Cheng

AU - Hawke, David H.

AU - Wang, Shouyu

AU - Zhang, Yanyan

AU - Wei, Yongkun

AU - Ma, Guolin

AU - Park, Peter K.

AU - Zhou, Jianwei

AU - Zhou, Yan

AU - Hu, Zhibin

AU - Zhou, Yubin

AU - Marks, Jeffery R.

AU - Liang, Han

AU - Hung, Mien Chie

AU - Lin, Chunru

AU - Yang, Liuqing

PY - 2016/1/28

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N2 - Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

AB - Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

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The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer

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