The long noncoding RNA NEAT1 and nuclear paraspeckles are up-regulated by the transcription factor HSF1 in the heat shock response

S Mohammad Lellahi,Ingrid Arctander Rosenlund,Annica Hedberg,Liv Torill Kiær,Ingvild Mikkola,Erik Knutsen,Maria Perander

doi:10.1074/jbc.ra118.004473

Abstract

The long noncoding RNA (lncRNA) NEAT1 (nuclear enriched abundant transcript 1) is the architectural component of nuclear paraspeckles, and it has recently gained considerable attention as it is abnormally expressed in pathological conditions such as cancer and neurodegenerative diseases. NEAT1 and paraspeckle formation are increased in cells upon exposure to a variety of environmental stressors and believed to play an important role in cell survival. The present study was undertaken to further investigate the role of NEAT1 in cellular stress response pathways. We show that NEAT1 is a novel target gene of heat shock transcription factor 1 (HSF1) and is up-regulated when the heat shock response pathway is activated by sulforaphane (SFN) or elevated temperature. HSF1 binds specifically to a newly identified conserved heat shock element in the NEAT1 promoter. In line with this, SFN induced the formation of NEAT1-containing paraspeckles via an HSF1-dependent mechanism. HSF1 plays a key role in the cellular response to proteotoxic stress by promoting the expression of a series of genes, including those encoding molecular chaperones. We have found that the expression of HSP70, HSP90, and HSP27 is amplified and sustained during heat shock in NEAT1-depleted cells compared with control cells, indicating that NEAT1 feeds back via an unknown mechanism to regulate HSF1 activity. This interrelationship is potentially significant in human diseases such as cancer and neurodegenerative disorders.

Highlights

The long noncoding RNA NEAT1 is the architectural component of nuclear paraspeckles, and it has recently gained considerable attention as it is abnormally expressed in pathological conditions such as cancer and neurodegenerative diseases
We show that NEAT1 is a novel target gene of heat shock transcription factor 1 (HSF1) and is up-regulated when the heat shock response pathway is activated by sulforaphane (SFN) or elevated temperature
We show that NEAT1 is up-regulated in response to heat shock demonstrating that up-regulation of NEAT1 is a general event in the heat shock response

Summary

To whom correspondence should be addressed

NEAT1 was found to be transcriptionally activated by HIF2␣ in response to hypoxia in cancer cells and, more recently, reported as a p53 target gene that prevents replication stress and DNA damage induced by mutagenic agents and oncogenes [13, 15, 18, 19]. The heat shock response is attenuated when HSF1 is released from the promoters of its target genes and either degraded or re-engaged into the HSF1repressive multichaperone complex by a negative feedback mechanism [21, 36]. We report that the isothiocyanate compound sulforaphane (SFN) induces NEAT1 expression and paraspeckle formation in MCF7 cells This is not dependent on the Keap1– NRF2 pathway but on binding and transcriptional activation of the NEAT1 promoter by HSF1. We demonstrate that the expression of HSP70, HSP90, and HSP27 is enhanced and sustained in the heat shock response in NEAT1 knockdown cells, compared with control cells

Results

Discussion

Experimental procedures