FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases.
The role of the Forkhead transcription factor FOXO3a in processes that promote tumor metastasis is poorly defined. Here, we show that depletion of FOXO3a from cancer cells leads to decreased tumor size specifically due to attenuated invasive migration. During tumor progression, an increase in tumor mass is concomitant with serum deprivation prior to tumor angiogenesis. We show that nuclear retention of FOXO3a due to serum starvation results in greatly increased cancer cell invasion. Exploration of the mechanism by which FOXO3a promotes invasive migration revealed that it induces the expression of matrix metalloproteinase 9 (MMP-9) and MMP-13, both of which have been causally linked to the invasion and progression of numerous human solid tumors. Our results link Forkhead transcription factors to a previously unexplored function in cancer progression by promoting extracellular matrix degradation, allowing tumors to invade neighboring tissues and ultimately metastasize to distant organs.
Storz
Peter
P
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Building, Jacksonville, FL 32224, USA. storz.peter@mayo.edu
Döppler
Heike
H
Copland
John A
JA
Simpson
Kaylene J
KJ
Toker
Alex
A
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018874:Spheroids, Cellular / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9