Gavin S Johnson1, Jia Li1, Laura M Beaver2,3, W Mohaiza Dashwood1, Deqiang Sun1, Praveen Rajendran1, David E Williams2,4, Emily Ho2,3, Roderick H Dashwood1,5,6,7. 1. Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, TX, USA. 2. Linus Pauling Institute, Oregon State University, Corvallis, OR, USA. 3. School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA. 4. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA. 5. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA. 7. Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, TX, USA.
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.
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 humancolon 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 humancolon 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: Lauren L Atwell; Laura M Beaver; Jackilen Shannon; David E Williams; Roderick H Dashwood; Emily Ho Journal: Curr Pharmacol Rep Date: 2015-04-01
Authors: Eunah Kim; William H Bisson; Christiane V Löhr; David E Williams; Emily Ho; Roderick H Dashwood; Praveen Rajendran Journal: Curr Top Med Chem Date: 2016 Impact factor: 3.295
Authors: Brian N Chorley; Michelle R Campbell; Xuting Wang; Mehmet Karaca; Deepa Sambandan; Fatu Bangura; Peng Xue; Jingbo Pi; Steven R Kleeberger; Douglas A Bell Journal: Nucleic Acids Res Date: 2012-05-11 Impact factor: 16.971
Authors: Ian M Copple; Wouter den Hollander; Giulia Callegaro; Fiona E Mutter; James L Maggs; Amy L Schofield; Lucille Rainbow; Yongxiang Fang; Jeffrey J Sutherland; Ewa C Ellis; Magnus Ingelman-Sundberg; Stephen W Fenwick; Christopher E Goldring; Bob van de Water; James L Stevens; B Kevin Park Journal: Arch Toxicol Date: 2018-11-13 Impact factor: 5.153