LHX6 acts as a novel potential tumour suppressor with epigenetic inactivation in lung cancer.
LHX6 acts as a novel potential tumour suppressor with epigenetic inactivation in lung cancer.
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LHX6 作为一种新型潜在肿瘤抑制因子，在肺癌中具有表观遗传失活作用
DOI：
10.1038/cddis.2013.366
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发表时间：
2013-10-24
影响因子：
9
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中科院分区：
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LIM同源盒区6(LHX6)是一种可能的转录调节因子，控制神经和淋巴样细胞的分化和发育。然而，LHX6在癌症发生中的作用在很大程度上仍不清楚。最近，我们发现LHX6在肺癌中发生了高甲基化。在本研究中，我们分析了它在肺癌中的表观遗传调控、生物学功能以及相关的分子机制。通过甲基化特异性聚合酶链式反应和亚硫酸氢盐基因组测序来评估甲基化状态。检测LHX6mRNA水平与甲基化状态的关系。在体外和体内研究LHX6的表达对肿瘤发生的影响。LHX6在无甲基化的正常肺组织中很容易表达，但在肺癌细胞系和高甲基化状态的组织中表达下调或沉默。用脱甲基剂5-氮杂-2‘-脱氧胞苷处理肺癌细胞后，LHX6的表达恢复。此外，56%(52/93)的肺癌组织中LHX6基因高甲基化，而正常肺组织中未检测到LHX6高甲基化(0/20)。在肺癌细胞株95D和H358中，强制表达LHX6抑制细胞活力、集落形成和迁移，诱导细胞凋亡和G1/S阻滞，并抑制其在裸鼠体内的成瘤作用。另一方面，通过RNA干扰抑制LHX6的表达，促进细胞增殖，抑制细胞凋亡和细胞周期停滞。这些作用与上调p21和p53，下调bc-2、cyClinD1、c-myc、CD44和MMP7表达有关。综上所述，我们的结果提示LHX6可能是肺癌中的一个具有表观遗传沉默的肿瘤抑制基因。
LIM homeobox domain 6 (LHX6) is a putative transcriptional regulator that controls the differentiation and development of neural and lymphoid cells. However, the function of LHX6 in cancer development remains largely unclear. Recently, we found that LHX6 is hypermethylated in lung cancer. In this study, we analysed its epigenetic regulation, biological functions, and related molecular mechanisms in lung cancer. Methylation status was evaluated by methylation-specific PCR and bisulfite genomic sequencing. LHX6 mRNA levels were measured in relation to the methylation status. The effects of LHX6 expression on tumourigenesis were studied in vitro and in vivo. LHX6 was readily expressed in normal lung tissues without methylation, but was downregulated or silenced in lung cancer cell lines and tissues with hypermethylation status. Treatment of lung cancer cells with the demethylating agent 5-aza-2′-deoxycytidine restored LHX6 expression. Moreover, LHX6 hypermethylation was detected in 56% (52/93) of primary lung cancers compared with none (0/20) of the tested normal lung tissues. In lung cancer cell lines 95D and H358, forced expression of LHX6 suppressed cell viability, colony formation, and migration, induced apoptosis and G1/S arrest, and inhibited their tumorigenicity in nude mice. On the other hand, knockdown of LHX6 expression by RNA interference increased cell proliferation and inhibited apoptosis and cell cycle arrest. These effects were associated with upregulation of p21 and p53, and downregulation of Bcl-2, cyclinD1, c-myc, CD44, and MMP7. In conclusion, our results suggest that LHX6 is a putative tumour suppressor gene with epigenetic silencing in lung cancer.