Oncotarget:同济大学张帆教授课题组揭示组蛋白去甲基化酶KDM1A促进
2016年4月9日，国际肿瘤学学术期刊《Oncotarget》杂志上在线发表了同济大学生命科学与技术学院和上海市肺科医院临床转化中心张帆课题组题为“KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells”的研究成果。生命科学与技术学院2012级硕士研究生孔令芝和上海市肺科医院胸外科的张鹏博士为论文共同第一作者。 张帆研究员为论文的通讯作者。
肺癌是我国发展最快和致死率最高的癌症之一， 非小细胞肺癌约占所有肺癌的80%。目前，尽管有包括放疗，化疗，和靶向药物治疗等多种治疗手段，约75%的患者发现时已处于中晚期，5年生存率很低。因此，深入研究肺癌侵袭转移的机制，并发现潜在的药物靶点显得尤为重要和紧迫。
表观遗传直接调控肿瘤的发生，发展，侵袭和转移。很多组蛋白修饰酶在非小细胞肺癌中表达异常升高。通过对公共数据库中大量肺癌样本的生物信息学分析和开展相关生物学实验，我们首次揭示了组蛋白去甲基化酶KDM1A/LSD1促进非小细胞肺癌侵袭和转移的一个新机制：KDM1A通过移除特异的组蛋白修饰, H3K4me2 (组蛋白3第4位赖氨酸的二甲基化), 来沉默TIMP3(一种基质金属蛋白酶的抑制蛋白)基因的转录, 导致细胞外基质(ECM)中基质金属蛋白酶MMP2的表达增加，和细胞内JNK (c-Jun N-terminal kinase) 蛋白激酶活性的增强，从而促进非小细胞肺癌的侵袭和转移。我们还验证了KDM1A小分子抑制剂2-PCPA对阻断EGFR突变的肺癌细胞的生长和侵袭比对Kras突变的肺癌细胞有更加显著的作用，为表观遗传治疗肺癌 (epigenetic therapy) 提供理论依据。
图：组蛋白去甲基化酶KDM1A促进非小细胞肺癌侵袭转移新机制
原文链接：
KDM1A promotes tumor Cell invasion by silencing TIMP3 in non-small cell lung cancer cells
原文摘要：
Epigenetic regulation plays an important role in tumor metastasis. KDM1A is a histone demethylase specific for H3K4me2/me1 demethylation, and has been found to be overexpressed in many cancers, including non-small cell lung cancer (NSCLC). However, the role of KDM1A in lung cancer remains unclear. Here, we show that KDM1A promotes cancer metastasis in NSCLC cells by repressing TIMP3 (tissue inhibitor of metalloproteinase 3) expression. Consistently with this, overexpression of TIMP3 inhibited MMP2 expression and JNK phosphorylation, both of which are known to be important for cell invasion and migration. Importantly, knockdown of TIMP3 in KDM1A-deficient cells rescued the metastatic capability of NSCLC cells. These findings were also confirmed by pharmacological inhibition assays. We further demonstrate that KDM1A removes H3K4me2 at the promoter of TIMP3, thus repressing the transcription of TIMP3. Finally, high expression of KDM1A and low expression of TIMP3 significantly correlate with a poor prognosis in NSCLC patients. This study establishes a mechanism by which KDM1A promotes cancer metastasis in NSCLC cells, and we suggest that KDM1A may be a potential therapeutic target for NSCLC treatment.
作者：张帆
