PO.MCB02.01 · 分子与细胞生物学
CtBP1/KAISO/TRIM28复合物对乳腺癌细胞自噬的多模式机制调控
Multimodal mechanistic control of autophagy by the CtBP1/KAISO/TRIM28 Complex in breast cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
自噬在乳腺癌进展中发挥着情境依赖性的作用，可交替促进或抑制肿瘤存活。然而，自噬的转录和代谢调控机制仍知之甚少。在此，我们鉴定出CtBP1/Kaiso/Trim28转录调控复合物是一个关键的代谢感受器，它协调细胞核内自噬基因的转录调控与细胞质中自噬机器的结构调控。我们证明，该CtBP1/Kaiso/Trim28复合物响应葡萄糖可利用性介导对自噬的多模式调控。跨管腔型（MCF7）和三阴性（MDA-MB-231）乳腺癌细胞的全基因组染色质占位分析（CNR-seq）和转录组分析（RNA-seq）揭示，CtBP1在关键自噬相关基因（包括ULK1、MTOR、VPS34和TFEB）的启动子处引导复合物组装。CtBP1或Kaiso的缺失导致这些靶基因失调，凸显了它们在维持自噬平衡中的协同作用。邻近连接实验在细胞核和细胞质中均检测到CtBP1/Kaiso/Trim28复合物，凸显它们与LC3等自噬组分共同调控自噬体形成与稳定性的“兼职”功能。其中若干复合物表现出葡萄糖依赖的动态变化，将代谢通量直接与自噬调控相联系。总之，这些发现揭示了一种此前未被认识的、与CtBP1相关的多模式机制，它将代谢信号与自噬的转录和结构调控相整合。CtBP1、Kaiso和Trim28之间明确的协调作用在乳腺癌中确立了一个关键的代谢-自噬轴，并提示了靶向CtBP1介导的代谢适应以治疗耐药性肿瘤的新策略。
查看英文原文 English abstract
Autophagy plays a context-dependent role in breast cancer progression, alternately promoting or suppressing tumor survival. However, the transcriptional and metabolic mechanisms for autophagy remain poorly understood. Here, we identify a CtBP1/Kaiso/Trim28 transcriptional regulatory complex as a key metabolic sensor that coordinates both transcriptional control of autophagy genes in the nucleus and structural regulation of autophagic machinery in the cytoplasm. We demonstrate that this CtBP1/Kaiso/Trim28 complex mediates multimodal control of autophagy in response to glucose availability. Genome-wide chromatin occupancy (CNR-seq) and transcriptomic profiling (RNA-seq) across luminal (MCF7) and triple-negative (MDA-MB-231) breast cancer cells reveal that CtBP1 directs complex assembly at promoters of key autophagy-related genes, including ULK1 , MTOR , VPS34 , and TFEB . Loss of CtBP1 or Kaiso leads to de-regulation of these targets, underscoring their cooperative role in maintaining autophagic balance. Proximity ligation assays detect CtBP1/Kaiso/Trim28 complexes in both nucleus and cytoplasm, highlighting their “moonlighting” function together with autophagic components such as LC3 in regulating autophagosome formation and stability. Several of these complexes display glucose-dependent dynamics, directly linking metabolic flux to autophagic regulation. Together, these findings uncover a previously unrecognized CtBP1-linked multimodal mechanism that integrates metabolic signals with both transcriptional and structural control of autophagy. The defined coordination between CtBP1, Kaiso, and Trim28 establishes a critical metabolic-autophagy axis in breast cancer and suggests new therapeutic strategies targeting CtBP1-mediated metabolic adaptation in therapy-resistant tumors.
利益披露 Disclosure
Y. Lee, None.