Oncogenic DMTF1β promotes cancer cell motility by regulating autophagy through ULK1 stabilization.

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.