Expanding Epigenetic Mechanisms of Sulforaphane in Colorectal Cancer: Pseudogenes and Protein Acetylation

Abstract

Two major hallmarks of cancer cells are their ability to sustain proliferative signaling and evade growth suppressors. This can occur when the cell loses transcriptional control of key growth genes through epigenetic mechanisms, such as histone and nonhistone modification, and dysregulation of non-coding RNAs. There is clinical interest in using small molecules to target these epigenetic mechanisms in order to prevent or reverse the dysregulation of the key cancer growth genes. Sulforaphane (SFN) is a dietary isothiocyanate that exhibits anticancer activity through a variety of mechanisms, such as the activation of the antioxidant response pathway, and through histone deacetylase (HDAC) inhibition. This dissertation examines two distinct mechanisms of SFN’s effect on epigenetic control of gene transcription. First, SFN induces NMRAL2P which is the first functional pseudogene to be identified as a direct target of Nrf2, and as a downstream regulator of Nrf2-dependent NQO1 induction. Second, SFN causes the acetylation of Cell Cycle and Apoptosis Regulator 2 (CCAR2) through inhibition of HDAC3. This, in turn, decreases β-Catenin nuclear localization and activity, reducing the expression of oncogenes MYC and MMP7. Also, SFN works in combination with JQ1, an inhibitor of acetylation readers, to further prevent cancer cell growth.