Interleukin enhancer‐binding factor 2 promotes cell proliferation and DNA damage response in metastatic melanoma

Abstract

Background 1q21.3 amplification, which is frequently observed in metastatic melanoma, is associated with cancer progression. Interleukin enhancer‐binding factor 2 ( ILF2 ) is located in the 1q21.3 amplified region, but its functional role or contribution to tumour aggressiveness in cutaneous melanoma is unknown. Methods In silico analyses were performed using the TCGA SKCM dataset with clinical annotations and three melanoma microarray cohorts from the GEO datasets. RNA in situ hybridisation and immunohistochemistry were utilised to validate the gene expression in melanoma tissues. Four stable melanoma cell lines were established for in vitro ILF2 functional characterisation. Results Our results showed that the ILF2 copy number variation (CNV) is positively correlated with ILF2 mRNA expression ( r = 0.68, p < .0001). Additionally, ILF2 expression is significantly increased with melanoma progression ( p < .0001), and significantly associated with poor overall survival for metastatic melanoma patients ( p = .026). The overexpression of ILF2 (ILF2‐OV) promotes proliferation in metastatic melanoma cells, whereas ILF2 knockdown decreases proliferation by blocking the cell cycle. Mechanistically, we demonstrated the interaction between ILF2 and the splicing factor U2AF2, whose knockdown reverses the proliferation effects mediated by ILF2‐OV. Stage IIIB–C melanoma patients with high ILF2 ‐ U2AF2 expression showed significantly shorter overall survival ( p = .024). Enhanced ILF2/U2AF2 expression promotes a more efficient DNA‐damage repair by increasing RAD50 and ATM mRNA expression. Paradoxically, metastatic melanoma cells with ILF2‐OV were more sensitive to ATM inhibitors. Conclusion Our study uncovered that ILF2 amplification of the 1q21.3 chromosome is associated with melanoma progression and triggers a functional downstream pathway in metastatic melanoma promoting drug resistance.

ILF2 Contributes to Hyperproliferation of Keratinocytes and Skin Inflammation in a KLHDC7B-DT-Dependent Manner in Psoriasis

“…ILF2, also known as nuclear factor 45 (NF45), is crucial for cell growth and the inflammatory response ( Du et al, 2019 ). Recent studies have shown that ILF2 can promote cell proliferation and the inflammatory response ( Jia et al, 2020 ; Zhang et al, 2021 ). ILF2 forms a complex with the 90 kDa interleukin enhancer binding factor 3 (NF90, ILF3) ( Zhao et al, 2005 ; Kuwano et al, 2008 ).…”

Pancancer Analyses Reveal Genomics and Clinical Characteristics of the SETDB1 in Human Tumors

“…Chromosome 1q gains occurred in various human cancers, such as LUAD, LIHC, OV, BRCA, and multiple myeloma [ 32 , 34 , 35 ]. Chromosome 1q21.3 abnormalities are related to breast cancer recurrence, and they can promote cell proliferation and DNA damage response in metastatic melanoma [ 35 , 36 ]. SETDB1 is located in the 1q21.3 region that encodes a histone methyltransferase which regulates transcriptional repression, histone methylation, and gene silencing [ 37 , 38 ].…”

Serine hydroxymethyltransferase 2 (SHMT2) potentiates the aggressive process of oral squamous cell carcinoma by binding to interleukin enhancer-binding factor 2 (ILF2)

“…The reduced cell viability and increased apoptosis rates observed in our experiments following SHMT2 knockdown were partially reversed by ILF2 overexpression. Additionally, upregulation of ILF2 was also testified to exacerbate cell invasion and metastasis in melanoma and to regulate EMT-related genes in pancreatic cancer PANC-1 cells [ 47 , 50 ]. In our experiments, ILF2 served as a promoter in the invasion, migration, and EMT process in SHMT2-knockdown CAL-27 cells.…”