Abstract
Simple SummaryA growing body of evidence indicates that stem cell-associated molecular features, collectively known as stemness, are biologically important in cancer development and progression, and negatively associate with anticancer immunity. The aim of our study was to investigate the association between TRIM28 level and melanoma stemness accompanied by low antitumor immune response. Furthermore, we aimed to evaluate potential value for TRIM28 in predicting stem-like melanoma phenotype. Our results indicate that TRIM28 might facilitate the “stemness high/immune low” melanoma phenotype by attenuating interferon signaling leading to a worse prognosis for melanoma patients. TRIM28 emerged as a regulator Interferon Regulatory Factor family of transcription factors’ expression, mediating epigenetic repression of IRF family members in “stemness high/immune low” melanomas.TRIM28 emerged as a guard of the intrinsic “state of cell differentiation”, facilitating self-renewal of pluripotent stem cells. Recent reports imply TRIM28 engagement in cancer stem cell (CSC) maintenance, although the exact mechanism remains unresolved. TRIM28 high expression is associated with worse melanoma patient outcomes. Here, we investigated the association between TRIM28 level and melanoma stemness, and aligned it with the antitumor immune response to find the mechanism of “stemness high/immune low” melanoma phenotype acquisition. Based on the SKCM TCGA data, the TRIM28 expression profile, clinicopathological features, expression of correlated genes, and the level of stemness and immune scores were analyzed in patient samples. The biological function for differentially expressed genes was annotated with GSEA. Results were validated with additional datasets from R2: Genomics Analysis and Visualization Platform and in vitro with a panel of seven melanoma cell lines. All statistical analyses were accomplished using GraphPad Prism 8. TRIM28HIGH-expressing melanoma patients are characterized by worse outcomes and significantly different gene expression profiles than the TRIM28NORM cohort. TRIM28 high level related to higher melanoma stemness as measured with several distinct scores and TRIM28HIGH-expressing melanoma cell lines possess the greater potential of melanosphere formation. Moreover, TRIM28HIGH melanoma tumors were significantly depleted with infiltrating immune cells, especially cytotoxic T cells, helper T cells, and B cells. Furthermore, TRIM28 emerged as a good predictor of “stemness high/immune low” melanoma phenotype. Our data indicate that TRIM28 might facilitate this phenotype by direct repression of interferon signaling. TRIM28 emerged as a direct link between stem cell-like phenotype and attenuated antitumor immune response in melanoma, although further studies are needed to evaluate the direct mechanism of TRIM28-mediated stem-like phenotype acquisition.
Highlights
TRIM28 (Tripartite Motif-containing 28), known as KAP1 (KRAB-Associated Protein 1)or TIF1-β (Transcriptional Intermediary Factor 1β), was previously shown to be involved in many aspects of cell homeostasis [1]
We analyzed the association of TRIM28 expression with clinicopathological features of skin cutaneous melanoma (SKCM) patients in TCGA data (Table 1 and Table S1) and observed that TRIM28HIGH patients harbored higher frequency of fraction genome altered (FGA) than TRIM28NORM cohort (p = 1.46e-3)
As gene repression requires the assembly of a methylation-dependent silencing complex that contains TRIM28 protein, we further looked at the methylation of interferon regulatory factor (IRF) promoters
Summary
TRIM28 (Tripartite Motif-containing 28), known as KAP1 (KRAB-Associated Protein 1)or TIF1-β (Transcriptional Intermediary Factor 1β), was previously shown to be involved in many aspects of cell homeostasis [1]. TRIM28 (Tripartite Motif-containing 28), known as KAP1 (KRAB-Associated Protein 1). As a cofactor for an abundant family of KRAB-ZNF (Krüppel associated box (KRAB) domain Zinc Finger Proteins) transcription factors, TRIM28 mediates the repression of a vast number of target genes [2,3]. TRIM28 takes part in the DNA damage response pathway [4], safeguards the genome stability through inhibition of retrotransposition [5], stimulates the epithelial-to-mesenchymal transition (EMT) [6], inhibits p53 activity [7], and induces the autophagosome formation that facilitates cell survival [8]. Recent studies revealed that TRIM28 safeguards stem cell phenotype at least partially by repressing the genes related to cell differentiation and inducing stemness markers [10]. All the above-mentioned functions of TRIM28 are frequently harnessed by cancer cells to promote cancer development and progression
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