The histone demethylase lysine-specific demethylase-1–mediated epigenetic silence of KLF2 contributes to gastric cancer cell proliferation, migration, and invasion

摘要

Gastric cancer is one of the most common malignancies and leading causes of cancer-related death worldwide. An increasing number of evidence has revealed that gastric tumorigenesis is a multistage pathological state, and epigenetic alterations are considered to play critical roles in the etiology of gastric cancer. Lysine-specific demethylase-1, a histone demethylase, has been linked to malignancy in several human cancers and considered to epigenetically regulate many tumor suppressor genes during tumorigenesis and cancer progression. However, its role and underlying targets in gastric cancer are still unclear. In this study, we detected the lysine-specific demethylase-1 expression level in gastric cancer tissues and cell lines and investigated the function and mechanism of lysine-specific demethylase-1 in the gastric cancer. The in vitro analysis shows that knockdown of lysine-specific demethylase-1 significantly inhibits gastric cancer cell proliferation, migration, and invasion and induces cell cycle G1 phase arrest and cell apoptosis. In vivo assays determine that lysine-specific demethylase-1 downregulation represses gastric cancer cell tumorigenesis. Mechanistic investigation reveals that tumor suppressor KLF2 is a key downstream target of lysine-specific demethylase-1 in gastric cancer. These findings indicate that lysine-specific demethylase-1 is an important oncogene in gastric cancer, and lysine-specific demethylase-1-mediated epigenetic repression of KLF2 plays a critical role in gastric cancer development and progression, which supports lysine-specific demethylase-1 as a potential therapeutic target in this disease.