Hong Yuxin, Ma Hehua, Yang Haoyi, Zhu Yuning, Wei Yuan, Xu Zhenzhen, Zhang Yuwen, Jin Dandan, Chen Zhiyou, Song Wei, Li Juan
Department of Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Front Pharmacol. 2024 Aug 30;15:1447830. doi: 10.3389/fphar.2024.1447830. eCollection 2024.
mA modification is a crucial epigenetic regulatory mechanism in diffuse large B-cell lymphoma (DLBCL). Low-dose cardiotonic drugs have been shown to induce apoptosis in DLBCL cells through epigenetic modulation. However, the involvement of the cardiotonic drug ouabain in the malignant progression of DLBCL remains unclear. Our study revealed that ouabain indeed contributes to the malignant progression of DLBCL through mA modification. Through qPCR analysis, we observed a negative correlation between ouabain concentration and the expression levels of the demethylase ALKBH5 and the mA-binding protein IGF2BP2 in DLBCL cells. Furthermore, high expression levels of ALKBH5 and IGF2BP2 were identified in both the GEO database and DLBCL patient tissue samples. Notably, elevated ALKBH5 and IGF2BP2 promoted cell proliferation both and . Inhibition of their expression rendered DLBCL cells more sensitive to ouabain treatment, resulting in significant suppression of cell proliferation, G1/S phase cell cycle arrest, and increased apoptosis. In summary, our results clarify that the demethylase ALKBH5 and the mA-binding protein IGF2BP2 are involved in the malignant progression of DLBCL, and that the cardiotonic drug ouabain can inhibit the proliferation of DLBCL cells by inhibiting the expression of ALKBH5 and IGF2BP2, which provides new insights into the targeted treatment of DLBCL.
N6-甲基腺嘌呤（m6A）修饰是弥漫性大B细胞淋巴瘤（DLBCL）中一种关键的表观遗传调控机制。低剂量强心药物已被证明可通过表观遗传调控诱导DLBCL细胞凋亡。然而，强心药物哇巴因在DLBCL恶性进展中的作用仍不清楚。我们的研究表明，哇巴因确实通过m6A修饰促进DLBCL的恶性进展。通过qPCR分析，我们观察到DLBCL细胞中哇巴因浓度与去甲基化酶ALKBH5和m6A结合蛋白IGF2BP2的表达水平呈负相关。此外，在GEO数据库和DLBCL患者组织样本中均鉴定出ALKBH5和IGF2BP2的高表达水平。值得注意的是，ALKBH5和IGF2BP2的升高均促进细胞增殖。抑制它们的表达使DLBCL细胞对哇巴因治疗更敏感，导致细胞增殖受到显著抑制、G1/S期细胞周期阻滞以及细胞凋亡增加。总之，我们的结果表明，去甲基化酶ALKBH5和m6A结合蛋白IGF2BP2参与了DLBCL的恶性进展，并且强心药物哇巴因可通过抑制ALKBH5和IGF2BP2的表达来抑制DLBCL细胞的增殖，这为DLBCL的靶向治疗提供了新的见解。
