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RNAi screening identifies HAT1 as a potential drug target in esophageal squamous cell carcinoma
Liang Xue1, Jun Hou2, Qun Wang1
1Department of Thoracic Surgery, Zhongshan Hospital Shanghai 200032, China.
Abstract:
Esophageal carcinoma (EC) is one of the most fatal carcinomas of the gastrointestinal tract. Aberrant activity of histone acetyltransferases (HATs)/deacetylases (HDACs) play a critical role in carcinogenesis through the regulation of the genes involved in cell differentiation, proliferation, and apoptosis. However, cellular functions of HATs/HDACs in esophageal cancer and its molecular mechanisms remain unclear. An RNAi screen was used in this study to identify the histone acetyltransferases (HATs) and deacetylases (HDACs) that could be critical for the survival of EC cells. We demonstrated that HAT1 (histone acetyltransferase 1) was an important determinant to regulate the proliferation of human EC Eca-109 cells. Furthermore, we showed that the knockdown of HAT1 induced a G2/M cell cycle arrest, which was associated with the disruption of cell cycle-related events, including the decrease of cyclinD1 as well as alteration in cyclinB1 expression. The expression of HAT1 was validated to be higher in the primary tumors and adjacent tissue as compared to that of the normal esophageal tissue. Furthermore, we found that HAT1 expression was directly correlated with the poor tumor differentiation of EC tissue, which suggested that HAT1 played an important role in esophageal carcinoma and that it could be a novel EC therapeutic target.
Insights
Histone acetyltransferase 1 (HAT1) is crucial for esophageal carcinoma (EC) cell survival and proliferation. Targeting HAT1 may offer a new therapeutic strategy for this fatal gastrointestinal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Esophageal carcinoma (EC) is a highly fatal gastrointestinal cancer.
- Aberrant histone acetyltransferase (HAT) and deacetylase (HDAC) activity is implicated in carcinogenesis.
- The specific roles of HATs/HDACs in EC and their molecular mechanisms require further elucidation.
Purpose of the Study:
- To identify critical HATs and HDACs involved in esophageal cancer cell survival using an RNAi screen.
- To investigate the functional role and molecular mechanisms of identified HATs/HDACs in EC progression.
Main Methods:
- Conducted an RNAi screen to identify key HATs and HDACs in esophageal cancer (EC) cell survival.
- Utilized cell culture (Eca-109 cells) to examine the effects of HAT1 knockdown on cell cycle progression.
- Analyzed protein expression of cell cycle regulators (cyclinD1, cyclinB1).
- Validated HAT1 expression levels in patient tumor tissues compared to normal esophageal tissues.
Main Results:
- Histone acetyltransferase 1 (HAT1) was identified as a critical regulator of EC cell proliferation.
- HAT1 knockdown induced a G2/M cell cycle arrest, impacting cyclinD1 and cyclinB1 expression.
- HAT1 expression is significantly elevated in EC primary tumors and adjacent tissues compared to normal esophageal tissue.
- Increased HAT1 expression correlates with poor tumor differentiation in EC patients.
Conclusions:
- HAT1 plays a significant role in the proliferation and progression of esophageal carcinoma.
- HAT1 is upregulated in EC tissues and associated with poor differentiation.
- HAT1 represents a potential novel therapeutic target for esophageal carcinoma treatment.
