Abstract
Purpose :
Retinoblastoma (RB) is the most common primary childhood ocular cancer. Due to interactions between RB and other proteins, RB1 loss can result in abnormal gene expression through transcriptional or epigenetic mis-regulation. Aberrant epigenetic changes are a hallmark in cancer and lysine specific demethylase 1 (Lsd1) is overexpressed in many tumors (PMCID:20333681). As the retina develops, Lsd1 is highly expressed in postmitotic retinal cells undergoing terminal differentiation and inhibition of Lsd1 prevents photoreceptor development (PMCID:26298666; PMCID:PMC6827424). Because many hallmark features of retinoblastoma tumors, such as rosettes and fleurettes mimic photoreceptors differentiation and Lsd1 is involved in the differentiation of those cell types, we investigated the role of Lsd1 in retinoblastoma tumors.
Methods :
We performed immunohistochemistry staining on human retinoblastoma samples for LSD1, Ki67, and caspase 3 as well as H&E staining. We also performed staining on mouse retinoblastoma samples for LSD1, Ki67, Caspase 3, Rhodopsin, and S-OPSIN as well as H&E. Additionally, we will treat RB cell lines (Y79 and WERI) with LSD1 and HDAC inhibitors to determine their effectiveness to kill cancerous cells.
Results :
In human RB samples, Lsd1 is expressed throughout the tumor and normal retina; however, quantification using Fiji shows statistically higher expression in the tumor compared to normal retina. In particular Lsd1 expression seems to be correlated with proliferating tumor cells, as indicated by Ki67 staining, and inversely correlated with apoptotic cells, as indicated by Caspase 3 staining. In the mouse RB samples, we see the same correlation in the tumor between Lsd1+ cells and Ki67+ cells; however, these tumors are located in the INL rather than the ONL suggesting a difference in cell origin from human RB tumors.
Conclusions :
As epigenetic dysregulation and overexpression of Lsd1 exists in numerous non-ocular cancers, we investigated Lsd1 as a potential biomarker in RB. Cancers related to RB, such as medulloblastoma, neuroblastoma, and glioblastoma, have shown decreased tumor cell viability and overall better survival prognosis when treated with Lsd1 inhibitors along or in combination with HDAC inhibitors. Thus, we believe Lsd1 inhibition is a promising treatment area to explore in RB.
This is a 2020 ARVO Annual Meeting abstract.