Co-targeting of specific epigenetic regulators in combination with CDC7 potently inhibit melanoma growth,iScience

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Co-targeting of specific epigenetic regulators in combination with CDC7 potently inhibit melanoma growth
iScience ( IF 4.6 ) Pub Date : 2022-07-15 , DOI: 10.1016/j.isci.2022.104752
Suresh Chava ₁ , Suresh Bugide ₁ , Parmanand Malvi ₁ , Romi Gupta _{1,

2}

Affiliation

Melanoma is a highly aggressive skin cancer that frequently metastasizes, but current therapies only benefit some patients. Here, we demonstrate that the serine/threonine kinase cell division cycle 7 (CDC7) is overexpressed in melanoma, and patients with higher expression have shorter survival. Transcription factor ELK1 regulates CDC7 expression, and CDC7 inhibition promotes cell cycle arrest, senescence, and apoptosis, leading to inhibition of melanoma tumor growth and metastasis. Our chemical genetics screen with epigenetic inhibitors revealed stronger melanoma tumor growth inhibition when XL413 is combined with the EZH2 inhibitor GSK343 or BRPF1/2/3 inhibitor OF1. Mechanistically, XL413 with GSK343 or OF1 synergistically altered the expression of tumor-suppressive genes, leading to higher apoptosis than the single agent alone. Collectively, these results identify CDC7 as a driver of melanoma tumor growth and metastasis that can be targeted alone or in combination with EZH2 or BRPF1/2/3 inhibitors.

中文翻译：

特定表观遗传调节因子与 CDC7 联合靶向可有效抑制黑色素瘤生长

黑色素瘤是一种高度侵袭性的皮肤癌，经常发生转移，但目前的治疗方法仅对部分患者有益。在这里，我们证明丝氨酸/苏氨酸激酶细胞分裂周期7（CDC7）在黑色素瘤中过度表达，表达较高的患者生存期较短。转录因子ELK1调节CDC7表达，CDC7抑制促进细胞周期停滞、衰老和凋亡，从而抑制黑色素瘤肿瘤的生长和转移。我们使用表观遗传抑制剂进行的化学遗传学筛选显示，当 XL413 与 EZH2 抑制剂 GSK343 或 BRPF1/2/3 抑制剂 OF1 联合使用时，可产生更强的黑色素瘤肿瘤生长抑制作用。从机制上讲，XL413 与 GSK343 或 OF1 协同改变肿瘤抑制基因的表达，导致比单独使用单一药物更高的细胞凋亡。总的来说，这些结果表明 CDC7 是黑色素瘤肿瘤生长和转移的驱动因素，可以单独靶向或与 EZH2 或 BRPF1/2/3 抑制剂联合靶向。

更新日期：2022-07-15

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