Proliferative and Metabolic Reprogramming by the Lysine-Specific Demethylase 1 in Hepatocellular Carcinoma

Lysine-specific demethylase 1 (LSD1) mediates chromatin remodeling by demethylating histone 3 lysine 4 and 9 (H3K4/K9), resulting in gene activation and suppression, respectively. Overexpression of LSD1 in various cancers, including hepatocellular carcinoma (HCC), contributes to cancer progression and malignancy.

In the present study, we show that pharmacological or siRNA-mediated LSD1 inhibition in hepatoma cells leads to altered H3K4/K9 methylation and to cell cycle arrest. Notably, transcriptomics by ultra-deep RNA sequencing and comprehensive proteomics by mass spectrometry, both linked to pathway analysis, revealed a definite impact of LSD1 on cell cycle progression and lipid metabolism. Subsequent chromatin immunoprecipitation (ChIP) followed by whole genome sequencing provided evidence of alterations in the histone methylation signature and LSD1 binding at the promoter sites of genes, involved in proliferation and lipogenesis, that are markedly downregulated after LSD1 inhibition. Noteworthy, ChIP-PCR assays confirmed changes in histone methylation and LSD1 binding at the promoter sites of metabolic genes such as FABP5 and proliferative genes such as PLK1, indicating that they are direct targets of LSD1 regulation. To investigate the effects of LSD1 in vivo, we induced hepatocarcinogenesis based on metabolic liver disease using a DEN/high-fat diet mouse model. Pharmacological inhibition of LSD1 resulted in weight loss, low fat accumulation, and significant reduction in tumor growth and in the number of proliferative Ki67-positive cells.

In conclusion, this study highlights that LSD1 is an important mediator in cell cycle control that affects HCC progression not only through cell cycle arrest but also through metabolic and lipid dysregulation.

Publication History

Article published online:
23 January 2024