A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells.

Abstract

SCOPE:

The anticancer agent sulforaphane (SFN) acts via multiple mechanisms to modulate gene expression, including the induction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent signaling and the inhibition of histone deacetylase activity. Transcriptomics studies were performed in SFN-treated human colon cancer cells and in nontransformed colonic epithelial cells in order to pursue new mechanistic leads.

METHODS AND RESULTS:

RNA-sequencing corroborated the expected changes in cancer-related pathways after SFN treatment. In addition to NAD(P)H quinone dehydrogenase 1 (NQO1) and other well-known Nrf2-dependent targets, SFN strongly induced the expression of Loc344887. This noncoding RNA was confirmed as a novel functional pseudogene for NmrA-like redox sensor 1, and was given the name NmrA-like redox sensor 2 pseudogene (NMRAL2P). Chromatin immunoprecipitation experiments corroborated the presence of Nrf2 interactions on the NMRAL2P genomic region, and interestingly, NMRAL2P also served as a coregulator of NQO1 in human colon cancer cells. Silencing of NMRAL2P via CRISPR/Cas9 genome-editing protected against SFN-mediated inhibition of cancer cell growth, colony formation, and migration.

CONCLUSION:

NMRAL2P is the first functional pseudogene to be identified both as a direct transcriptional target of Nrf2, and as a downstream regulator of Nrf2-dependent NQO1 induction. Further studies are warranted on NMRAL2P-Nrf2 crosstalk and the associated mechanisms of gene regulation.

• Authors: Gavin S Johnson, Jia Li, Laura M Beaver, W Mohaiza Dashwood, Deqiang Sun, Praveen Rajendran, David E Williams, Emily Ho, Roderick H Dashwood
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 61 Issue 4 (04 2017) ISSN: 1613-4133 [Electronic] Germany
• PMID: 27860235 (Publication Type: Journal Article)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Anticarcinogenic Agents
• Isothiocyanates
• NF-E2-Related Factor 2
• Sulfoxides
• Thiocyanates
• NAD(P)H Dehydrogenase (Quinone)
• sulforaphane

Topics

• Anticarcinogenic Agents (pharmacology)
• Cell Transformation, Neoplastic
• Colon (metabolism)
• Colonic Neoplasms (drug therapy, genetics)
• Gene Expression (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Isothiocyanates (pharmacology, therapeutic use)
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Pseudogenes
• Signal Transduction (drug effects)
• Sulfoxides
• Thiocyanates (pharmacology)