TC10-like (TCL) is a
small GTPase that has been implicated in
carcinogenesis. Elevated TCL expression has been observed in many different types of
cancers although the underlying epigenetic mechanism is poorly understood. Here we report that TCL up-regulation was associated with high
malignancy in both human
colorectal cancer biopsy specimens and in cultured
colorectal cancer cells.
Hypoxia, a pro-metastatic stimulus, up-regulated TCL expression in HT-29 cells. Further studies revealed that
myocardin-related
transcription factor A (MRTF-A) promoted migration and invasion of HT-29 cells in a TCL-dependent manner. MRTF-A directly bound to the proximal TCL promoter in response to
hypoxia to activate TCL transcription.
Chromatin immunoprecipitation (ChIP) assay showed that
hypoxia stimulation specifically enhanced acetylation of
histone H4K16 surrounding the TCL promoter, which was abolished by MRTF-A depletion or inhibition. Mechanistically, MRTF-A interacted with and recruited the H4K16
acetyltransferase hMOF to the TCL promoter to cooperatively regulate TCL transcription. hMOF depletion or inhibition attenuated
hypoxia-induced TCL expression and migration/invasion of HT-29 cells. In conclusion, our data identify a novel MRTF-A-hMOF-TCL axis that contributes to
colorectal cancer metastasis.