You Ji Hyeon, Lee Jaewang, Roh Jong-Lyel
Department of Otorhinolaryngology-Head Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.
Department of Otorhinolaryngology-Head Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.
Cancer Lett. 2021 Jun 1;507:40-54. doi: 10.1016/j.canlet.2021.03.013. Epub 2021 Mar 16.
Cancer cells evolve to survive as 'persister cells' resistant to various chemotherapeutic agents. Persister cancer cells retain mesenchymal traits that are vulnerable to ferroptosis by iron-dependent accumulation of lethal lipid peroxidation. Regulation of the KDM5A-MPC1 axis might shift cancer cells to have mesenchymal traits via epithelial-mesenchymal transition process. Therefore, we examined the therapeutic potentiality of KDM5A-MPC1 axis regulation in promoting ferroptosis in erlotinib-tolerant persister head and neck cancer cells (erPCC). ErPCC acquired mesenchymal traits and disabled antioxidant program that were more vulnerable to ferroptosis inducers of RSL3, ML210, sulfasalazine, and erastin. GPX4 and xCT suppression caused increased sensitivity to ferroptosis in vivo models of GPX4 genetic silencing. KDM5A expression increased and MPC1 expression decreased in erPCC. KDM5A inhibition increased MPC1 expression and decreased sensitivity to ferroptosis inducers in erPCC. MPC1 suppression increased vulnerability to ferroptosis in vitro and in vivo by retaining mesenchymal traits and glutaminolysis. Low expression of MPC1 was associated with low overall survival from the TCGA data. Our data suggest that regulation of the KDM5A-MPC1 axis contributes to promoting cancer ferroptosis susceptibility.
癌细胞演化为作为对各种化疗药物具有抗性的“持久细胞”而存活。持久癌细胞保留了间充质特征，这些特征因铁依赖性致死性脂质过氧化的积累而容易发生铁死亡。KDM5A-MPC1轴的调节可能通过上皮-间充质转化过程使癌细胞具有间充质特征。因此，我们研究了KDM5A-MPC1轴调节在促进耐厄洛替尼的持久头颈癌细胞（erPCC）铁死亡中的治疗潜力。ErPCC获得了间充质特征并禁用了抗氧化程序，这些特征对RSL3、ML210、柳氮磺胺吡啶和厄拉替尼的铁死亡诱导剂更敏感。在GPX4基因沉默的体内模型中，GPX4和xCT的抑制导致对铁死亡的敏感性增加。在erPCC中，KDM5A表达增加而MPC1表达降低。KDM5A抑制增加了erPCC中MPC1的表达并降低了对铁死亡诱导剂的敏感性。MPC1抑制通过保留间充质特征和谷氨酰胺分解增加了体外和体内对铁死亡的易感性。根据TCGA数据，MPC1的低表达与低总生存率相关。我们的数据表明，KDM5A-MPC1轴的调节有助于提高癌症铁死亡易感性。
