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Oncogenic DMTF1β promotes cancer cell motility by regulating autophagy through ULK1 stabilization
Jun Xu1,2, Nicolas J Niklaus1,2, Anna M Schläfli1
1Institute of Tissue Medicine and Pathology, Division of Experimental Pathology, University of Bern, Switzerland.
Abstract:
The cyclin D binding Myb-like Transcription Factor 1 (DMTF1) is a haploinsufficient tumor suppressor in various tumors. Alternative splicing generates a dominant negative, truncated version of full-length DMTF1α, named DMTF1β. DMTF1β has so far been described as an oncogene in breast cancer development. However, a clear understanding of how DMTF1β contributes to carcinogenesis remains unknown. Analyzing DMTF1β protein expression in breast cancer cell lines, as well as a highly metastatic prostate cancer cell line, confirmed a positive correlation between DMTF1β expression and tumorigenic potential. Specifically, knocking down DMTF1β in aggressive MDA-MB-231 breast and PC3MPRO4 prostate cancer cells significantly reduced wound closure and tissue invasion. β-specific interactome and RNA-sequencing studies in DMTF1β overexpressing and knockdown cells, respectively, suggest that DMTF1β expression is associated with the autophagy recycling pathway. Depleting DMTF1β levels in cancer cells significantly decreased autophagic flux. Moreover, inhibiting autophagy led to decreased migration of DMTF1β expressing breast cancer cells. Mechanistically, DMTF1β protein interacts with and stabilizes the key autophagy protein ULK1. In conclusion, we identified a novel function for the alternatively spliced DMTF1 gene product in autophagy-dependent cancer cell motility.
Insights
The truncated DMTF1β protein drives cancer cell movement by stabilizing ULK1, a key player in the autophagy pathway. This finding reveals a novel mechanism in cancer progression and motility.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The cyclin D binding Myb-like Transcription Factor 1 (DMTF1) acts as a tumor suppressor.
- Alternative splicing produces DMTF1β, a truncated, dominant-negative form implicated as an oncogene in breast cancer.
- The precise role of DMTF1β in carcinogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of DMTF1β in cancer progression and identify its molecular mechanisms.
- To explore the association between DMTF1β expression and cancer cell motility.
- To elucidate the functional link between DMTF1β and the autophagy pathway.
Main Methods:
- Analysis of DMTF1β protein expression in breast and prostate cancer cell lines.
- Gene knockdown experiments to assess the impact of DMTF1β on cell migration and invasion.
- Interactome and RNA-sequencing studies to identify DMTF1β-associated pathways.
- Investigation of DMTF1β's interaction with autophagy-related proteins, specifically ULK1.
Main Results:
- DMTF1β expression positively correlates with tumorigenic potential in cancer cell lines.
- Knockdown of DMTF1β significantly reduced migration and invasion in aggressive breast and prostate cancer cells.
- DMTF1β expression is linked to the autophagy pathway, and its depletion impairs autophagic flux.
- DMTF1β interacts with and stabilizes the autophagy protein ULK1, promoting cancer cell motility.
Conclusions:
- DMTF1β promotes cancer cell motility through a novel mechanism involving the autophagy pathway.
- Stabilization of ULK1 by DMTF1β is a key step in enhancing autophagy-dependent cancer cell migration.
- This study identifies an important role for alternatively spliced DMTF1 variants in cancer progression.
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