创作:Lexi 审核:Lexi 2019年11月18日
  • NF-kB持续活化是结肠肿瘤生长标志物,细胞周期蛋白依赖性激酶(CDKs)是重要的细胞周期调节因子;
  • NFE2L3转录因子连接了NF-κB信号与CDK1活化,从而驱动结肠癌细胞增殖;
  • NFE2L3在结肠腺癌中高表达,NFE2L3沉默可抑制结肠癌细胞系HCT116和HT29增殖,并抑制小鼠移植瘤生长;
  • NF-kB转录因子家族亚基RELA(p65) 正向调控NFE2L3表达,有助于其促肿瘤效应;
  • 抑制NFE2L3表达可增强DUX4表达水平,DUX4是CDK1的直接抑制剂。
NF-kB转录因子在许多癌症发展过程中起到关键作用,包括炎症、生长、血管生成、侵袭、转移和耐药性。NF-kB还控制多种关键细胞周期调节因子的水平,如cyclin D1、MYC和周期蛋白依赖性激酶(CDKs)。NF-kB过表达与结直肠癌(CRC)患者较差的总生存密切相关。CNC转录因子在多种细胞进程中起到关键作用,包括应激反应和致癌进程,其最广为人知的家族成员是NFE2L2(NRF2)蛋白。NFE2L3(NRF3)是NFE2L2的同系物,目前对其研究较少,其功能尚不清楚。最新发表在Cell Reports的一项研究旨在探索影响NFE2L3功能的细胞网络,其揭示了NFE2L3在控制结肠癌细胞生长的NF-kB信号通路中起着关键作用。
Cell Reports [IF:8.109]

NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor



2019-11-05, Article

Abstract & Authors:展开

Constitutive nuclear factor κB (NF-κB) activation is a hallmark of colon tumor growth. Cyclin-dependent kinases (CDKs) are critical cell-cycle regulators, and inhibition of CDK activity has been used successfully as anticancer therapy. Here, we show that the NFE2L3 transcription factor functions as a key regulator in a pathway that links NF-κB signaling to the control of CDK1 activity, thereby driving colon cancer cell proliferation. We found that NFE2L3 expression is regulated by the RELA subunit of NF-κB and that NFE2L3 levels are elevated in patients with colon adenocarcinoma when compared with normal adjacent tissue. Silencing of NFE2L3 significantly decreases colon cancer cell proliferation in vitro and tumor growth in vivo. NFE2L3 knockdown results in increased levels of double homeobox factor 4 (DUX4), which functions as a direct inhibitor of CDK1. The discovered oncogenic pathway governing cell-cycle progression may open up unique avenues for precision cancer therapy.

First Authors:
Marina Bury,Benjamin Le Calvé

Correspondence Authors:
Volker Blank

All Authors:
Marina Bury,Benjamin Le Calvé,Frédéric Lessard,Thomas Dal Maso,James Saliba,Carine Michiels,Gerardo Ferbeyre,Volker Blank