Journal Article

KLF9-dependent ROS regulate melanoma progression in stage-specific manner

Fink, Emily E., Jowdy, Peter, Rodriguez, Cesar, Kandel, Eugene S., Bagati, Archis, Kolesnikova, Masha, Nikiforov, Mikhail A., Box, Neil F., Paragh, Gyorgy, Udartseva, Olga O., Berman, Albert E., Roll, Matthew V., Lipchick, Brittany C., Bianchi-Smiraglia, Anna, Yun, Dong Hyun, Soengas, Maria S., Moparthy, Sudha, Bshara, Wiam, Wolff, David W., Han, Zhannan, Kozlova, Nadezhda I.

2019

Overview

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 CA mice, where Braf V600E causes premalignant melanocytic hyperplasia, and Braf CA /Pten −/− mice, where Braf V600E and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in Braf CA mice but did not affect formation and growth of Braf CA /Pten −/− primary melanomas. It also, as expected, promoted Braf CA /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 CA and Braf CA /Pten −/− melanocytic cells. Mechanistically, we demonstrated that BRAF V600E 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 V600E . PTEN depletion in BRAF V600E -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 V600E 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/31 / 13/89 / 45/15 / 631/67/2327 / 631/80/304 / Acetylcysteine - adverse effects / Adult / Aged / Aged, 80 and over / Animal models / Animals / Antioxidants / Antioxidants (Nutrients) / Apoptosis / B cells / Cancer / Cancer metastasis / Cell Biology / Cell growth / Cell proliferation / Cysteine / Cystine / Development and progression / Genes / Genetic aspects / Health aspects / Human Genetics / Humans / Hyperplasia / Internal Medicine / Kruppel-Like Transcription Factors - genetics / Kruppel-Like Transcription Factors - metabolism / Mediation / Medicine / Medicine & Public Health / Melanocytes / Melanocytes - drug effects / Melanocytes - metabolism / Melanocytes - pathology / Melanoma / Melanoma - genetics / Melanoma - metabolism / Melanoma - pathology / Melanoma, Experimental - chemically induced / Melanoma, Experimental - metabolism / Melanoma, Experimental - pathology / Metastases / Metastasis / Mice, Knockout / Middle Aged / Novels / Oncology / Oxidative stress / Phenotypes / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / PTEN protein / Reactive oxygen species / Reactive Oxygen Species - metabolism / Skin Neoplasms - metabolism / Skin Neoplasms - pathology / Transcription / Transcription (Genetics) / Tumors