Expression of HDAC9 in lung cancer--potential role in lung carcinogenesis
Koji Okudela1, Hideaki Mitsui1, Takehisa Suzuki1
1Department of Pathology, Yokohama City University Graduate School of Medicine 3-9, Future, Kanazawaku, 236-0004, Yokohama, Japan.
Abstract:
Our previous studies identified important molecules involved in lung carcinogenesis through a comprehensive search for the downstream targets of oncogenic KRAS, and these findings suggested that an investigation into the downstream targets of oncogenic KRAS might represent a useful strategy for elucidating the common molecular bases of lung cancer. Among the downstream targets of oncogenic KRAS, a focus was placed on HDAC9, a member of the histone deacetylase family, in the present study because epigenetic modification of DNA or the histone proteins is known to play an important role in carcinogenesis. The immunohistochemical expression of HDAC9 was examined in surgically resected primary lung cancers (130 adenocarcinoma, 49 squamous cell carcinomas, one large cell carcinoma, and 6 small cell carcinomas) and potential associations between its expression level and pathologic factors were analyzed. The results showed that HDAC9 expression levels were lower in lung cancer cells than in non-tumor epithelial cells, and were also significantly lower in adenocarcinomas among the histological types. Moreover, HDAC9 expression levels were significantly lower in adenocarcinomas with lymphatic canal involvement. The restoration of HDAC9 in lung cancer cells losing its expression severely attenuated their growth activity in vitro. These results suggest that HDAC9 may be a suppressor and its downregulation might promote the progression process, especially in lung adenocarcinomas.
Insights
Histone deacetylase 9 (HDAC9) is downregulated in lung cancer, particularly adenocarcinomas. Restoring HDAC9 suppressed tumor cell growth, suggesting it acts as a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Oncogenic KRAS signaling pathways are crucial in lung carcinogenesis.
- Epigenetic modifications, including histone acetylation, play a significant role in cancer development.
- Histone deacetylase 9 (HDAC9) is a key epigenetic regulator identified as a downstream target of oncogenic KRAS.
Purpose of the Study:
- To investigate the expression levels of HDAC9 in primary lung cancers.
- To analyze the association between HDAC9 expression and clinicopathological factors.
- To evaluate the functional role of HDAC9 in lung cancer cell growth.
Main Methods:
- Immunohistochemical analysis of HDAC9 expression in 186 surgically resected primary lung tumors (130 adenocarcinoma, 49 squamous cell carcinoma, etc.).
- Statistical analysis to correlate HDAC9 expression with histological type, lymphatic invasion, and other pathological factors.
- In vitro experiments to assess the effect of HDAC9 restoration on lung cancer cell proliferation.
Main Results:
- HDAC9 expression was significantly lower in lung cancer cells compared to non-tumor epithelial cells.
- Lower HDAC9 levels were observed in lung adenocarcinomas and specifically in those with lymphatic canal involvement.
- Restoration of HDAC9 expression in lung cancer cells markedly inhibited their in vitro growth.
Conclusions:
- HDAC9 functions as a tumor suppressor in lung cancer.
- Downregulation of HDAC9 may promote lung adenocarcinoma progression.
- HDAC9 represents a potential therapeutic target for lung adenocarcinoma.
