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

Publication Title

Clin Transl Med

Authors

Xiaoqing Zhang, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica, CaliforniaFollow
Matias A Bustos, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica, CaliforniaFollow
Rebecca Gross, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.Follow
Romela Irene Ramos, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USAFollow
Teh-Ling Takeshima, Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA 90404, USA.Follow
Gordon B Mills
Qiang Yu
Dave S B Hoon, Department of Translational Molecular Medicine, Providence Saint John's Health Center, Saint John's Cancer Institute, Santa Monica, CaliforniaFollow

Document Type

Article

Publication Date

10-1-2021

Keywords

california; sjci; santa monica; ATM; DNA damage response; ILF2; RAD50; U2AF2; 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.

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology