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oai:repisalud.isciii.es:20.500.12105/253682025-12-18T13:01:29Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Bagati, Archis author Moparthy, Sudha author Fink, Emily E author Bianchi-Smiraglia, Anna author Yun, Dong Hyun author Kolesnikova, Masha author Udartseva, Olga O author Wolff, David W author Roll, Matthew V author Lipchick, Brittany C author Han, Zhannan author Kozlova, Nadezhda I author Jowdy, Peter author Berman, Albert E author Box, Neil F author Rodriguez, Cesar author Bshara, Wiam author Kandel, Eugene S author Soengas, MS author Paragh, Gyorgy author Nikiforov, Mikhail A author 2019-05 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 mice, where Braf causes premalignant melanocytic hyperplasia, and Braf/Pten mice, where Braf and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in Braf mice but did not affect formation and growth of Braf/Pten primary melanomas. It also, as expected, promoted Braf/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 Braf and Braf/Pten melanocytic cells. Mechanistically, we demonstrated that BRAF 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. PTEN depletion in BRAF-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 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. Oncogene . 2019 May;38(19):3585-3597. Oncogene https://pmc.ncbi.nlm.nih.gov/articles/PMC6939757/pdf/nihms-1031560.pdf 30664687 https://hdl.handle.net/20.500.12105/25368 KRUPPEL-LIKE FACTORS OXIDATIVE STRESS MITOCHONDRIAL THIOREDOXIN KEAP1-NRF2 PATHWAY kINASE SENESCENCE BRAF PHOTOPROTECTION DYSREGULATION ACTIVATION KLF9-dependent ROS regulate melanoma progression in stage-specific manner.