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KLF9-dependent ROS regulate melanoma progression in stage-specific manner.
- Source :
-
Oncogene [Oncogene] 2019 May; Vol. 38 (19), pp. 3585-3597. Date of Electronic Publication: 2019 Jan 21. - Publication Year :
- 2019
-
Abstract
- Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: Braf <superscript>CA</superscript> mice, where Braf <superscript>V600E</superscript> causes premalignant melanocytic hyperplasia, and Braf <superscript>CA</superscript> /Pten <superscript>-/-</superscript> mice, where Braf <superscript>V600E</superscript> and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in Braf <superscript>CA</superscript> mice but did not affect formation and growth of Braf <superscript>CA</superscript> /Pten <superscript>-/-</superscript> primary melanomas. It also, as expected, promoted Braf <superscript>CA</superscript> /Pten <superscript>-/-</superscript> metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in Braf <superscript>CA</superscript> and Braf <superscript>CA</superscript> /Pten <superscript>-/-</superscript> melanocytic cells. Mechanistically, we demonstrated that BRAF <superscript>V600E</superscript> signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAF <superscript>V600E</superscript> . PTEN depletion in BRAF <superscript>V600E</superscript> -melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAF <superscript>V600E</superscript> signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.
- Subjects :
- Acetylcysteine adverse effects
Adult
Aged
Aged, 80 and over
Animals
Humans
Kruppel-Like Transcription Factors genetics
Melanocytes drug effects
Melanocytes metabolism
Melanocytes pathology
Melanoma genetics
Melanoma metabolism
Melanoma, Experimental chemically induced
Melanoma, Experimental metabolism
Melanoma, Experimental pathology
Mice, Knockout
Middle Aged
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins B-raf metabolism
Skin Neoplasms metabolism
Kruppel-Like Transcription Factors metabolism
Melanoma pathology
Reactive Oxygen Species metabolism
Skin Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 38
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 30664687
- Full Text :
- https://doi.org/10.1038/s41388-019-0689-6