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

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: BrafCA mice, where BrafV600E causes premalignant melanocytic hyperplasia, and BrafCA/Pten−/− mice, where BrafV600E and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in BrafCA mice 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 BrafCA and BrafCA/Pten−/− melanocytic cells. Mechanistically, we demonstrated that BRAFV600E signaling transcriptionally upregulated KLF9 and 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 BRAFV600E 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.

Dexamethasone induces aberrant macrophage immune function and apoptosis

“…Altered levels of caspase-3, caspase-9, and Cyt-c following overexpression of KLF9 in accordance with exposure to Dex were also revealed. In addition, it has been reported that KLF9 causes intracellular ROS accumulation by suppressing transcription of the thioredoxin reductase 2 gene, which plays a pivotal role in defense against oxidative damage (7,19). In the present study, it was revealed that KLF9 could promote the accumulation of intracellular ROS, thus inducing macrophage apoptosis.…”

“…Several studies have demonstrated that tumor-derived KLF9 may act as a tumor suppressor by promoting apoptosis (8,19,20). Decreased KLF9 suppresses oxidative stress and apoptosis, subsequently promoting cancer progression (7). In fact, KLF9 overexpression in tumor cells can induce apoptosis via excessive oxidative stress production.…”

“…Krüppel-like factor 9 (KLF9), also called basic transcription element-binding protein-1 (Bteb1), is a ubiquitously expressed member of the C2H2-type zinc finger family (7). A recent study suggested that KLF9 plays an important role in regulating animal development and differentiation of various cell types (8).…”

“…Current experimental evidence indicates that KLF9 plays a key hormone-dependent role in liver gluconeogenesis (9). Notably, a recent study indicated that KLF9 is induced by NF-E2-like basic leucine zipper transcriptional activator (Nrf2), thereby promoting cell oxidative stress (7).…”

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

“…Bagati and colleagues shed further light on such a complex role by suggesting a double and stage-specific role for ROS in melanoma. Indeed, while mechanistically demonstrating that ablation of Klf9, a pro-oxidant transcriptional regulator, promotes metastases in a Braf V600E ; Pten −/− GEMM of melanoma without affecting primary tumor growth, the authors also reasoned that Klf9 deficiency inhibits premalignant melanocytic hyperplasia in a Braf V600E -induced hyperplasia model (77).…”