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Published on: January 7, 2019
FOXD3 is a mutant B-RAF-regulated inhibitor of G(1)-S progression in melanoma cells
1Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
Abstract:
The forkhead box transcription factor FOXD3 is a stemness factor that prevents the production of melanocyte progenitors from the developing neural crest; however, its role in human cancers is not known. Transformation of melanocytes gives rise to melanoma. In two thirds of melanomas, the serine/threonine kinase B-RAF is mutated to a constitutively active form. Here, we show that FOXD3 levels are upregulated following attenuation of B-RAF and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) signaling in mutant B-RAF harboring human melanoma cells. This effect was selective because FOXD3 was not upregulated following MEK inhibition in wild-type B-RAF melanoma cells and mutant B-RAF thyroid carcinoma cells. Ectopic FOXD3 expression potently inhibited melanoma cell growth without altering mutant B-RAF activation of ERK1/2. Inhibition of cell growth was due to a potent G(1) cell cycle arrest and was associated with p53-dependent upregulation of p21(Cip1). FOXD3-induced cell cycle arrest was prevented by p53 depletion and, to a lesser extent, p21(Cip1) depletion. These studies show that FOXD3 is suppressed by B-RAF, uncover a novel role and mechanism for FOXD3 as a negative cell cycle regulator, and have implications for the repression of melanocytic lineage cells.
Insights
Forkhead box transcription factor FOXD3 suppresses melanoma cell growth by inducing cell cycle arrest. B-RAF signaling normally inhibits FOXD3, revealing a new role for this stemness factor in cancer.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Forkhead box transcription factor FOXD3 is a known stemness factor involved in neural crest development.
- Its role in human cancers, particularly melanoma, remains largely unknown.
- Melanoma often harbors mutations in the B-RAF kinase, leading to constitutive signaling.
Purpose of the Study:
- To investigate the role of FOXD3 in human melanoma.
- To determine the relationship between B-RAF signaling and FOXD3 expression.
- To elucidate the mechanism by which FOXD3 affects melanoma cell growth.
Main Methods:
- Analysis of FOXD3 expression in human melanoma cells with varying B-RAF mutational status.
- Manipulation of B-RAF and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) signaling pathways.
- Assessment of melanoma cell proliferation, cell cycle progression, and expression of cell cycle regulators (p53, p21Cip1) following FOXD3 modulation.
Main Results:
- FOXD3 expression is upregulated upon attenuation of B-RAF/MEK signaling specifically in mutant B-RAF melanoma cells.
- Ectopic expression of FOXD3 potently inhibits melanoma cell growth by inducing a G1 cell cycle arrest.
- This cell cycle arrest is dependent on p53 and associated with p21(Cip1) upregulation.
Conclusions:
- FOXD3 acts as a tumor suppressor in melanoma, independent of B-RAF-driven ERK signaling.
- B-RAF signaling suppresses FOXD3, and FOXD3 functions as a negative regulator of the cell cycle.
- These findings suggest therapeutic potential for targeting the B-RAF-FOXD3 axis in melanoma treatment.
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