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Updated: Apr 23, 2026
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Published on: October 27, 2020
TGF-β/SMAD4/14-3-3σ/TFEB axis promotes mesenchymal-epithelial transition and inhibits autophagy in colorectal cancer
Xiaoyan Chen1, Markus Winter1, Matjaz Rokavec1
1Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Thalkirchner Strasse 36, D-80337, Munich, Germany.
Abstract:
14-3-3σ is a p53-inducible gene with tumor suppressive properties and SMAD4 is a transcription factor encoded by a tumor suppressor gene, which is commonly inactivated in colorectal cancer (CRC). Here, 14-3-3σ was characterized as direct transcriptional target of SMAD4. TGF-β treatment of tumoroids derived from CRC patients and mouse models resulted in a SMAD4-dependent induction of 14-3-3σ. In murine, intestinal epithelia, the apical expression of 14-3-3σ was dependent on Smad4. Ectopic SMAD4 or 14-3-3σ promoted mesenchymal-to-epithelial transition (MET) and suppressed invasion, migration, and autophagy of CRC cells. As experimental inactivation of 14-3-3σ abolished these tumor-suppressive functions of SMAD4, 14-3-3σ mediates these effects of SMAD4. Inhibition of autophagy and promotion of MET by SMAD4 was mediated by inhibition of TFEB via binding and sequestration of TFEB by 14-3-3σ. The association of 14-3-3σ and TFEB was dependent on phosphorylation of the TFEB serine 211 residue, which is a target of mTORC1. Taken together, the TGF-β/SMAD4/14-3-3σ/TFEB axes characterized here antagonizes epithelial plasticity and autophagy. Thereby, it may ultimately suppress the progression of CRC and other types of cancer.
Insights
SMAD4 directly regulates 14-3-3σ, a tumor suppressor. This pathway inhibits cancer cell invasion, migration, and autophagy, potentially suppressing colorectal cancer (CRC) progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- 14-3-3σ exhibits tumor-suppressive properties and is induced by p53.
- SMAD4, a transcription factor, is frequently inactivated in colorectal cancer (CRC).
Purpose of the Study:
- To characterize 14-3-3σ as a direct transcriptional target of SMAD4.
- To elucidate the role of the SMAD4/14-3-3σ axis in regulating colorectal cancer cell behavior and tumor progression.
Main Methods:
- Analysis of tumoroids from CRC patients and mouse models.
- Investigating SMAD4-dependent gene expression and protein interactions.
- Assessing the impact of SMAD4 and 14-3-3σ on cell migration, invasion, autophagy, and epithelial-mesenchymal transition (EMT).
Main Results:
- SMAD4 directly induces 14-3-3σ expression in CRC tumoroids and murine intestinal epithelia.
- Ectopic SMAD4 or 14-3-3σ expression promotes mesenchymal-to-epithelial transition (MET) and suppresses CRC cell invasion, migration, and autophagy.
- 14-3-3σ mediates the tumor-suppressive functions of SMAD4 by inhibiting TFEB (Transcription Factor EB) through binding and sequestration, dependent on TFEB phosphorylation by mTORC1.
Conclusions:
- The TGF-β/SMAD4/14-3-3σ/TFEB signaling pathway antagonizes epithelial plasticity and autophagy.
- This axis plays a crucial role in suppressing colorectal cancer progression and may offer therapeutic targets for other cancers.
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