Deciphering the Role of LSD1 in Hepatocellular Carcinoma: Implications for Cell Proliferation and Energy Homeostasis

Lysine-specific demethylase 1 (LSD1) plays a pivotal role in chromatin structure regulation and transcriptional control through the demethylation of histone 3 lysine 4 or lysine 9, resulting in gene-specific activation or repression, respectively. LSD1 overexpression was shown in various cancer types, contributing to high malignancy. In our study we investigated the role of LSD1 role in hepatocellular carcinoma (HCC).

Global transcriptomics and proteomics analyses of hepatoma cells revealed significant alterations in cell cycle, mitochondrial, and lipid metabolism genes upon LSD1 inhibition. Consequently, LSD1 inhibition significantly impaired cell cycle progression, viability, and mitochondrial ATP and oxygen production. Importantly, using a metabolic-associated HCC mouse model by means of diethyl nitrosamine application and a high fat diet, we show a marked reduction in liver enzymes, fat accumulation, proliferation and tumor growth upon pharmacological LSD1 blockade. Moreover, expression profiling in clinical HCC samples of different etiologies demonstrated that LSD1 levels significantly correlated with the expression of cell cycle and the energy balance machinery.

In order to prove that a wide panel of genes involved in proliferation, mitochondrial respiration and lipid biogenesis are direct targets of LSD1 histone demethylation, we performed chromatin-immunoprecipitation followed by whole genome sequencing on hepatoma cells in response to conditional siRNA LSD1 inhibition. Indeed, LSD1 mediated alterations in the histone methylation status revealed its epigenetic transcriptional control . In conclusion, this study demonstrated that LSD1 promotes HCC progression by triggering proliferation and metabolic reprogramming, highlighting its potential as a therapeutic target for HCC treatment.

Publication History

Article published online:
20 January 2025