Roderick H. Dashwood, PhD

Director, Center for Epigenetics & Disease Prevention
Institute of Biosciences and Technology
Texas A&M College of Medicine, Houston, TX

 image of Dr. Roderick Dashwood
Abstract: 3,3’-Diindolylmethane (DIM) is a biologically active derivative of indole-3-carbinol, an anticancer agent from cruciferous vegetables. Early DIM research focused on xenobiotic metabolism changes linked to the inhibition of mammary and liver tumorigenesis [Wattenberg & Loub, Cancer Res 1978; Bradfield & Bjeldanes, J Toxicol Environ Health 1987; Dashwood et al., Cancer Res 1994]. Subsequent work implicated DIM in signaling pathways regulating cell division, apoptosis, and angiogenesis [reviewed by Licznerska & Baer-Dubowska, Adv Exp Med Biol 2016]. Research with DIM moved into the epigenetic realm with evidence for changes in histone deacetylase (HDAC) enzymes, chromatin modifiers, genome-wide DNA methylation, and miRNA networks [Li et al., Cancer Res 2010; Beaver et al., Toxicol Appl Pharmacol 2012; Wong et al., PLoS One 2014; Palomera-Sanchez et al., J Nutr Biochem 2017; Hanieh, Mol Cancer 2015]. Parallel investigations focused on sulforaphane (SFN), another anticancer agent from cruciferous vegetables [Zhang et al., PNAS 1992]. As an electrophile, SFN targets Keap1 to release Nrf2 into the nucleus [Yang et al., Semin Oncol 2016]. Among the Nrf2 target genes are enzymes that convert SFN into water-soluble metabolites that inhibit HDAC activity [Myzak et al., Cancer Res 2004]. SFN-cysteine and SFN-N-acetylcysteine metabolites target the HDAC3-SMaRT corepressor complex for inhibition/turnover, altering the acetylation status of both histone and non-histone proteins [Rajendran et al., Mol Cancer 2011; Rajendran et al., Epigenetics 2013; Rajendran et al., Clin Epigenetics 2015]. Transcriptomics (RNA-seq) also defined SFN-induced changes in noncoding RNAs, including repression of lncRNA LINC01116 in prostate cancer cells [Beaver et al., J Nutr Biochem 2017], and upregulation of a novel functional pseudogene, NMRAL2P, in colon cancer cells [Johnson et al., Mol Nutr Food Res 2017]. Clinical validation of these mechanistic targets is now ongoing in human volunteers.