SMC4的削弱引发的类休眠结直肠癌细胞具有低增殖和化疗耐药的特点。
The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity.
发表日期：2023 Jul 30
作者：
Xuedan Sun, Lifang He, Hong Liu, Rick Francis Thorne, Taofei Zeng, Liu Liu, Bo Zhang, Miao He, Yabin Huang, Mingyue Li, Enyi Gao, Mengyao Ma, Cheng Cheng, Fanzheng Meng, Chuandong Lang, Hairui Li, Wanxiang Xiong, Shixiang Pan, Delong Ren, Bingyi Dang, Yi Yang, Mian Wu, Lianxin Liu
来源：
Cell Metabolism
摘要：
对不利的环境条件，胚胎发育可能发生可逆的停滞，这个过程被称为休眠。最近的报道将这一现象与肿瘤对化疗的非遗传反应联系起来，但所涉及的机制尚不清楚。在这里，我们建立了SMC4在结直肠癌细胞转向休眠样状态中的多方面作用。SMC4的削减促进了三个投资阶段的糖酵解酶的表达，增加乳酸产量，同时抑制PGAM1。由此产生的高乳酸水平通过组蛋白乳酸化增加ABC转运蛋白的表达，使肿瘤细胞对化疗不敏感。SMC4作为PGAM1转录的共激活因子，并且SMC4和PGAM1的协同损失影响F-肌动蛋白的装配，诱导细胞分裂失败和多倍体，从而抑制细胞增殖。对非遗传化疗抗性机制的这些见解可能对该领域有重要意义，推动我们对肿瘤中有氧糖酵解功能的理解，可能为未来的治疗策略提供相关信息。版权所有 © 2023 Elsevier Inc. 保留所有权利。
In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.Copyright © 2023 Elsevier Inc. All rights reserved.