G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Francisco Exposito, Miriam Redrado, Diego Serrano, Silvia Calabuig-Fariñas, Aida Bao-Caamano, Sandra Gallach, Eloisa Jantus-Lewintre, Angel Diaz-Lagares, Aitor Rodriguez-Casanova, Juan Sandoval, Edurne San Jose-Eneriz, Javier Garcia, Esther Redin, Yaiza Senent, Sergio Leon, Ruben Pio, Rafael Lopez, Julen Oyarzabal, Antonio Pineda-Lucena, Xabier Agirre, Luis M Montuenga, Felipe Prosper, Alfonso Calvo
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Abstract

The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.

G9a/DNMT1 协同靶向抑制非小细胞肺癌的生长,并通过 SCARA5 和 AOX1 重编程肿瘤细胞,使其对抗癌药物做出反应。
近年来,非小细胞肺癌(NSCLC)患者的治疗策略有了明显改善,但仍有许多患者无法从中获益。因此,迫切需要新的治疗方法。在这项研究中,我们评估了联合靶向 G9a 和 DNMT1 酶的抗肿瘤疗效及其作为抗癌药物增敏剂的潜力。我们观察到,G9a和DNMT1在NSCLC中的共表达和过表达与不良预后有关。在一组人类和鼠类 NSCLC 细胞系中,与 CM-272 共同靶向 G9a/DNMT1 的药物可减少细胞增殖并诱导细胞死亡。此外,这些细胞的转录组经过重新编程,对化疗(顺铂)、靶向治疗(曲美替尼)和表观遗传学治疗(伏立诺他)具有高度响应性。在体内,CM-272能减少人和小鼠细胞衍生癌症模型中的肿瘤体积,顺铂能协同增强这种效果。CM-272诱导了SCARA5和AOX1的表达,发现这两种蛋白对于抗增殖反应至关重要,因为基因沉默会降低细胞毒性。此外,在 NSCLC 患者中,SCARA5 和 AOX1 的表达相互正相关,与 G9a 和 DNMT1 的表达成反比。SCARA5和AOX1的DNA启动子在NSCLC中存在高甲基化,SCARA5甲基化在NSCLC患者的肿瘤和液体活检中被鉴定为表观遗传生物标记物。因此,我们证明了联合靶向 G9a/DNMT1 是提高抗癌药物疗效的一种有前途的策略,而 SCARA5 甲基化可作为监测肿瘤进展的一种非侵入性生物标记物。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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