Abstract
Lysine specific demethylase 1A (LSD1) is an epigenetic modifier which interacts with various substrates and has diverse functions. Epigenetic dysregulation is emerging as a hallmark of cancer and thus, epigenetic inhibitors are a therapeutic target of interest. Earlier studies of organoid models show that LSD1 knockout (KO) organoids can grow in the absence of a WNT epithelial source (Paneth cells). In addition, LSD1 inhibition of intestinal organoids led to the expansion of the stem cell population. We demonstrate that LSD1 inhibition in a WNT driven organoid tumor model leads to morphological changes, namely an ellipsoid appearance as opposed to the spherical tumor organoid. We investigated the possibility that these change in morphology was related to changes in the cytoskeletal structure and we observed an increased expression of the actin binding protein Filamin A (FLNA) on LSD1 inhibition. A trend towards an increase in the expression of the WNT signalling pathway signal transducer protein β-catenin was observed. Another trend identified was an increase in the expression of the cell adherens junction protein E-cadherin which also displayed a cytoplasmic distribution as opposed to the predominantly membranal distribution seen in healthy intestinal epithelial cells. Whether the changes in morphology, WNT signalling pathway factors and cytoskeletal proteins are indicative of a reduction or an increase in characteristics favourable to tumor survival requires further in vivo studies.
