Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4

Abstract

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a−/− melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance

“…Regulatory malignancies of SALL4 are involved in multiple chromatin modification regulators [29]. As previously reported, epigenetic factors that interact with SALL4 include six types: the nucleosome remodeling deacetylase (NuRD) complex, which includes HDAC1 and HDAC2 [49,96]; DNA methyltransferases-1 (DNMT-1), DNMT-3A, DNMT-3B, DNMT-3 L, and methyl-CpG-binding domain 2 protein (MBD2) [18]; H3K4 methyltransferase MLL1 [92,97]; H3K36 methyltransferase Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1) [98,99]; H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1 L) [68,100]; and lysine-specific histone demethylase LSD1/KDM1A [49,94,101] (Figure 6B). Interestingly, SALL4 seems to interact with these epigenetic factors at different sites.…”

“…Anti-proliferative effects in glioma Inhibit Wnt/β-catenin signaling [11] Induce angiogenesis Active the VEGF-A gene [12] SALL2 Tumor suppressor Inhibit c-Myc gene [13] SALL3 Promote tumorigenesis SALL3 promoter hypermethylation [3] SALL4 Oncogene in glioma Induce epithelial-mesenchymal transition [14] Promote progression in lung cancer Activate EGFR by ERK1/2 signaling [15] Promote proliferation, migration, and invasion in breast cancer Activate Wnt/β-catenin signaling [16] Promote growth and invasion in osteosarcoma Sponge miR-107 [17] Promote invasiveness in melanoma Interact with the HDAC 2 and bind to invasiveness genes [18] Promote development in hepatocellular carcinoma Activate Wnt/β-catenin signaling [19] Promote metastasis in gastric cancer Activate the TGF-β/SMAD signaling [20]…”

“…Oncofetal SALL4, a zinc finger transcription factor [10,18], is an embryonic stem cell regulator involved in self-renewal and pluripotency [21]. SALL4 located in chromosome 20.q13.2 translates into two isoforms, SALL4A and SALL4B [10,22], which are a result of different internal splicing patterns in exon 2 [6,22,23].…”

“…Additionally, a recent study found that downregulation of SALL4 triggered pluripotency loss, leading to derepression of a set of AT-rich genes that promoted neuronal differentiation [24]. SALL4 is a potential target for the diagnosis and treatment of cancer [18,30]. It participates in the regulation of cell growth, cell cycle, and apoptosis via the expression of articulation-related genes, and it exerts biological effects as a transcription factor in the nucleus, where it plays a crucial role in the occurrence and development of various malignant tumors.…”

Genetic and Genomic Pathways of Melanoma Development, Invasion and Metastasis

“…Further, mutations are also insufficient to explain phenotypic plasticity in melanoma, including phenotype switching. Therefore, investigators have begun to employ epigenetic and epigenomic studies to explain phenotype plasticity and phenotype switching in melanoma [128][129][130][131][132][133][134][135][136][137]. These studies include chromatin remodeling, as well as genome-wide DNA methylation analysis, together with integrated transcriptomic analysis of protein-coding regions to investigate mechanisms that regulate phenotype switching between the invasive and non-invasive subtypes of cutaneous melanoma [108,133,138,139].…”