1. KLF9-dependent ROS regulate melanoma progression in stage-specific manner
- Author
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Bagati, Archis, Moparthy, Sudha, Fink, Emily E., Bianchi-Smiraglia, Anna, Yun, Dong Hyun, Kolesnikova, Masha, Udartseva, Olga O., Wolff, David W., Roll, Matthew V., Lipchick, Brittany C., Han, Zhannan, Kozlova, Nadezhda I., Jowdy, Peter, Berman, Albert E., Box, Neil F., Rodriguez, Cesar, Bshara, Wiam, Kandel, Eugene S., Soengas, Maria S., Paragh, Gyorgy, and Nikiforov, Mikhail A.
- 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: BrafCAmice, where BrafV600Ecauses premalignant melanocytic hyperplasia, and BrafCA/Pten−/−mice, where BrafV600Eand loss of Pteninduce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in BrafCAmice but did not affect formation and growth of BrafCA/Pten−/−primary melanomas. It also, as expected, promoted BrafCA/Pten−/−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 BrafCAand BrafCA/Pten−/−melanocytic cells. Mechanistically, we demonstrated that BRAFV600Esignaling transcriptionally upregulated KLF9and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAFV600E. PTEN depletion in BRAFV600E-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 BRAFV600Esignaling 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.
- Published
- 2019
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