HDAC10核质定位及其介导的自噬作用在肺癌中的功能和机制研究

肺癌是我国发病与死亡率最高的癌症，HDAC和自噬作用都在癌症中发挥重要作用并成为倍受关注的靶点。我们前期发现：1)HDAC10在肺癌中高表达并与生存率负相关，促进肺癌增殖并为其生存所必需；2)HDAC10在肺正常细胞中位于细胞核，但在肺癌细胞中位于细胞质；3)HDAC10促进肺癌细胞自噬作用并与自噬调节蛋白AKT和tubulin相互作用。本计划：1)研究HDAC10核质定位的机制及其胞质定位与细胞癌化的关系；2)鉴定肺癌细胞中与HDAC10相互作用的自噬相关蛋白并研究它们如何相互作用；3)研究HDAC10与相关自噬蛋白如何共同调节肺癌的自噬作用；4)研究HDAC10介导的自噬在肺癌增殖和生存中的作用。本项目从HDAC10的核质定位及其与Non-histone蛋白相互作用调节自噬这一新视角，研究其在自噬、肺癌发生、增殖和生存中的机制，探讨其能否作为肺癌治疗的新靶点，具有重要的理论和应用价值。

Lung cancer is the leading cause of cancer death in China. HDAC and autophagy both are implicated in cancer development and attractive therapeutic targets for lung cancer. We found that the expression of HDAC10 in lung cancer is higher than adjacent normal tissue and negatively correlates with survival rate. Our experimental data suggested that HDAC10 promotes lung cancer growth and is required for lung cancer survival. Interestingly, HDAC10 mainly resides in nucleus in normal lung epithelial cells but localizes to cytoplasm in lung cancer cells. We also found HDAC10 promotes autophage in lung cancer cells and interacts with AKT and tubulin, both are regulators of autophagy. We plan to 1) investigate how the localization of HDAC10 is regulated and the contribution of cytoplasmic HDAC10 to cell transformation; 2) identify autophagy-related proteins that interact with HDAC10 and characterize the biochemical interplay between HDAC10 and its interacting proteins; 3) investigate how the interplay of HDAC10 and its interaction proteins regulates autophagy in lung cancer cells; 4) evaluate the role of HDAC10 and its mediated autophagy in the cell growth and survival of lung cancer. The proposal uncovers the function and mechanism of HDAC10 in autophagy, cell growth and survival of lung cancer and reveals the potetial of HDAC10 as a novel therapeutic target for lung cancer.