TitleA functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsJohnson GS, Li J, Beaver LM, W Dashwood M, Sun D, Rajendran P, Williams DE, Ho E, Dashwood RH
JournalMol Nutr Food Res
Date Published2017 04
KeywordsAnticarcinogenic Agents, Cell Transformation, Neoplastic, Colon, Colonic Neoplasms, Gene Expression, Gene Expression Regulation, Humans, Isothiocyanates, NAD(P)H Dehydrogenase (Quinone), NF-E2-Related Factor 2, Pseudogenes, Signal Transduction, Thiocyanates

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.

Alternate JournalMol Nutr Food Res
PubMed ID27860235
PubMed Central IDPMC5380536
Grant ListP01 CA090890 / CA / NCI NIH HHS / United States
R01 CA080176 / CA / NCI NIH HHS / United States
R01 CA065525 / CA / NCI NIH HHS / United States
P30 ES023512 / ES / NIEHS NIH HHS / United States
R01 CA122959 / CA / NCI NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States