Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
Department of Cell Biology, Jagiellonian University, 31-007, Krakow, Poland.
Cell Death Differ. 2019 Oct;26(10):2100-2114. doi: 10.1038/s41418-019-0278-9. Epub 2019 Jan 28.
Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose Non-Fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of Zeste Homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2-based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death. We reveal a novel mechanism of action of EZH2 inhibition, alone and in combination with cisplatin, which induces immune signaling with the largest changes observed in interferon gamma (IFN-γ). This upregulation is a result of activated natural killer (NK) signaling as demonstrated by the increase in NK cell-associated genes MIP-1α, ICAM1, ICAM2, and CD86 in xenografts treated with EZH2 inhibitors. Conversely, EZH2 inhibition results in decreased expression of pluripotency markers, ALDH2 and CK5, and increased cell death. Our results reveal a novel sensitivity of muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations to EZH2 inhibition alone and in combination with cisplatin. This sensitivity is mediated through increased NK cell-related signaling resulting in tumor cell differentiation and cell death.
赖氨酸特异性脱甲基酶 6A（KDM6A）和 Switch/Sucrose Non-Fermentable（SWI/SNF）家族的成员已知可拮抗 Enhancer of Zeste Homolog 2（EZH2）的活性，EZH2 在肌肉浸润性膀胱癌中常过度表达，并与预后不良相关。在这里，我们提供证据表明，染色质修饰酶的改变，包括 KDM6A 和 SWI/SNF 复合物的成员，在肌肉浸润性膀胱癌中很常见。我们利用 KDM6A 和 SWI/SNF 复合物的功能丧失突变使膀胱癌细胞对基于 EZH2 的表观遗传治疗敏感，该治疗可激活免疫反应以驱动肿瘤细胞分化和死亡。我们揭示了 EZH2 抑制的一种新的作用机制，单独使用和与顺铂联合使用，可诱导免疫信号，干扰素 γ（IFN-γ）的变化最大。这种上调是由于自然杀伤（NK）信号的激活所致，这可以通过在 EZH2 抑制剂处理的异种移植物中 NK 细胞相关基因 MIP-1α、ICAM1、ICAM2 和 CD86 的增加来证明。相反，EZH2 抑制导致多能性标志物 ALDH2 和 CK5 的表达降低和细胞死亡增加。我们的结果揭示了具有 KMD6A 和 SWI/SNF 突变的肌肉浸润性膀胱癌细胞对 EZH2 抑制单独和与顺铂联合的新敏感性。这种敏感性是通过增加与 NK 细胞相关的信号传导介导的，从而导致肿瘤细胞分化和细胞死亡。
