Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.
JCI Insight. 2020 Apr 9;5(7):131486. doi: 10.1172/jci.insight.131486.
Development of chemotherapy resistance is a major problem in ovarian cancer. One understudied mechanism of chemoresistance is the induction of quiescence, a reversible nonproliferative state. Unfortunately, little is known about regulators of quiescence. Here, we identify the master transcription factor nuclear factor of activated T cells cytoplasmic 4 (NFATC4) as a regulator of quiescence in ovarian cancer. NFATC4 is enriched in ovarian cancer stem-like cells and correlates with decreased proliferation and poor prognosis. Treatment of cancer cells with cisplatin resulted in NFATC4 nuclear translocation and activation of the NFATC4 pathway, while inhibition of the pathway increased chemotherapy response. Induction of NFATC4 activity resulted in a marked decrease in proliferation, G0 cell cycle arrest, and chemotherapy resistance, both in vitro and in vivo. Finally, NFATC4 drove a quiescent phenotype in part via downregulation of MYC. Together, these data identify NFATC4 as a driver of quiescence and a potential new target to combat chemoresistance in ovarian cancer.
化疗耐药性的发展是卵巢癌的一个主要问题。耐药性的一个研究较少的机制是诱导静止，这是一种可逆的非增殖状态。不幸的是，关于静止的调节因子知之甚少。在这里，我们确定激活 T 细胞胞浆核因子 4（NFATC4）作为卵巢癌静止的调节因子。NFATC4 在卵巢癌类干细胞中富集，并与增殖减少和预后不良相关。顺铂处理癌细胞导致 NFATC4 核易位和 NFATC4 途径的激活，而抑制该途径则增加了化疗反应。NFATC4 活性的诱导导致体外和体内增殖明显减少、G0 细胞周期停滞和化疗耐药性。最后，NFATC4 通过下调 MYC 驱动静止表型。总之，这些数据表明 NFATC4 是静止的驱动因子，也是对抗卵巢癌化疗耐药性的一个潜在新靶点。
