Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Oncogene. 2020 Oct;39(41):6468-6479. doi: 10.1038/s41388-020-01449-y. Epub 2020 Sep 2.
Aberrations in epigenetic modulation dysregulate transcription, playing a critical role in the developmental process of tumors, including lung cancer. Aberrant levels of the histone 3 lysine-27 demethylase KDM6A have been found in cancer and are either positively or negatively associated with tumorigenesis and prognosis. However, the clinical relevance and functional role of KDM6A in lung cancer is largely unknown. We found that KDM6A protein expression was higher in NSCLC tissues than in the corresponding paracancer tissues and that high KDM6A expression was associated with poor patient prognosis. Furthermore, KDM6A knockdown in NSCLC cell lines markedly inhibited the tumorigenic phenotype both in vitro and in vivo. Mechanistically, KDM6A colocalized and cooperated with KMT2B to reprogram the transcriptional network via regulating the cancer pathway, in which abnormal activation of the Wnt pathway is the dominant factor. Interestingly, in NSCLC cell lines, H3K4me3 but not H3K27me2/3 or H3K4me1/2 was markedly altered upon KDM6A or KMT2B knockdown, indicating that KDM6A may act independently of H3K27 demethylases in NSCLC. Taken together, these results indicated that KDM6A or KMT2B may be a prognostic biomarker and promising therapeutic target in NSCLC.
表观遗传调控异常会扰乱转录，在肿瘤的发育过程中发挥关键作用，包括肺癌。在癌症中发现组蛋白 3 赖氨酸-27 去甲基化酶 KDM6A 的水平异常，并且与肿瘤发生和预后呈正相关或负相关。然而，KDM6A 在肺癌中的临床相关性和功能作用在很大程度上尚不清楚。我们发现，非小细胞肺癌组织中的 KDM6A 蛋白表达高于相应的癌旁组织，并且高 KDM6A 表达与患者预后不良相关。此外，在非小细胞肺癌细胞系中敲低 KDM6A 显著抑制了体外和体内的致瘤表型。在机制上，KDM6A 与 KMT2B 共定位并合作，通过调节癌症途径重塑转录网络，其中 Wnt 途径的异常激活是主要因素。有趣的是，在非小细胞肺癌细胞系中，KDM6A 或 KMT2B 敲低后，H3K4me3 而不是 H3K27me2/3 或 H3K4me1/2 明显改变，表明 KDM6A 可能在非小细胞肺癌中独立于 H3K27 去甲基化酶发挥作用。总之，这些结果表明，KDM6A 或 KMT2B 可能是非小细胞肺癌的预后生物标志物和有前途的治疗靶点。
