FHL1乙酰化修饰在肿瘤中的功能和分子机制研究

Protein acetylation abnormality plays an important role in tumorigenesis and tumor development.Therefore, protein acetylation modification becomes target of anti-tumor drugs development.We have reported that FHL1 protein is a tumor suppressor in breast cancer, liver cancer and lung cancer, and downregulated in various tumors. But the mechanism of FHL1 protein functioning as a tumor suppressor and its downregulation remains unclear.We found that FHL1 protein is acetylated and its inhibition on tumor cells growth and metastasis is acetylation dependent, and the stability of FHL1 protein is associated with acetylation. Based on these results, we will further investigate the cross-talk between acetylation and ubiquitination of FHL1 and the effect of FHL1 acetylation on tumor cell growth, invasion and metastasis. Using breast and liver cancer specimens, we will define the clinical significance of FHL1 acetylation. This study will lay a solid foundation for elucidating the molecular mechanisms of FHL1 protein as a tumor suppressor and looking for novel targets of tumor diagnosis and therapy.

蛋白质乙酰化修饰异常在肿瘤的发生发展中起重要作用，因此，蛋白质乙酰化修饰成为抗肿瘤药物开发的靶标。我们已经报道FHL1在乳腺癌、肝癌及肺癌中发挥抑癌基因的功能，并在多种肿瘤中表达下调，但FHL1发挥抑癌功能和在肿瘤中表达下降的机制还不清楚。我们的研究发现，FHL1蛋白存在乙酰化修饰，FHL1抑制肿瘤细胞的生长和侵袭依赖于其乙酰化修饰，且其乙酰化修饰与FHL1蛋白稳定性相关。本申请拟在此研究基础上，进一步确认FHL1乙酰化修饰与其泛素化修饰的相互调节及其分子机制；FHL1乙酰化在肿瘤细胞生长、侵袭和转移中的功能；利用乳腺癌及肝癌标本，检测FHL1乙酰化的临床意义，为阐明FHL1抑癌功能分子机制及发现新的诊断和治疗靶标打下坚实基础。