|Title||A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Johnson GS, Li J, Beaver LM, W Dashwood M, Sun D, Rajendran P, Williams DE, Ho E, Dashwood RH|
|Journal||Mol Nutr Food Res|
|Date Published||2017 04|
|Keywords||Anticarcinogenic 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 Journal||Mol Nutr Food Res|
|PubMed Central ID||PMC5380536|
|Grant List||P01 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