What question did this study set out to answer?

The research aims to elucidate the transcriptional and metabolic mechanisms governing autophagy in breast cancer cells.

April 5, 2026Cancer Research0 citations

Abstract 4670: Multimodal mechanistic control of autophagy by the CtBP1/KAISO/TRIM28 Complex in breast cancer cells

YLY.W. LeeNew York University KGKevin GardnerColumbia University Irving Medical Center

Key Points

The research aims to elucidate the transcriptional and metabolic mechanisms governing autophagy in breast cancer cells.
Identified the CtBP1/Kaiso/Trim28 complex as a metabolic regulator.
Utilized CNR-seq and RNA-seq for chromatin and transcriptomic profiling.
Studied both luminal (MCF7) and triple-negative (MDA-MB-231) breast cancer cell lines.
Conducted proximity ligation assays to examine complex presence in cells.
CtBP1 directs assembly at promoters of key autophagy genes such as ULK1, MTOR, and VPS34.
Loss of CtBP1 or Kaiso disrupts regulation of these targets.
Complexes show glucose-dependent dynamics linking metabolism to autophagic regulation.

Abstract

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. Citation Format: Young-Ho Lee, Kevin L. Gardner. Multimodal mechanistic control of autophagy by the CtBP1/KAISO/TRIM28 Complex in breast cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4670.

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