Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma. Choi Jiyeon,Zhang Tongwu,Vu Andrew,Ablain Julien,Makowski Matthew M,Colli Leandro M,Xu Mai,Hennessey Rebecca C,Yin Jinhu,Rothschild Harriet,Gräwe Cathrin,Kovacs Michael A,Funderburk Karen M,Brossard Myriam,Taylor John,Pasaniuc Bogdan,Chari Raj,Chanock Stephen J,Hoggart Clive J,Demenais Florence,Barrett Jennifer H,Law Matthew H,Iles Mark M,Yu Kai,Vermeulen Michiel,Zon Leonard I,Brown Kevin M Nature communications Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAF background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility. 10.1038/s41467-020-16590-1

Overexpression of human MX2 gene suppresses cell proliferation, migration, and invasion via ERK/P38/NF-κB pathway in glioblastoma cells. Wang Huanyu,Guan Qiang,Nan Yang,Ma Quanfeng,Zhong Yue Journal of cellular biochemistry In human, there are two myxovirus resistance genes-MX1 and MX2, which respectively encode MXA and MXB protein. For MXB, it was traditionally deemed to work in the progression of cell cycle and adjustment of nuclear import. Thus, we speculated that it might play important roles in tumor progression. The purpose of this study was to preliminarily explore the underlying functions and mechanism of the MX2 gene on glioblastoma multiforme. Quantitative reverse transcription polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), and transwell experiments were to detect the relative MX2 mRNA level and its biological functions on glioma cells, respectively. The data displayed that MX2 was obviously downregulated both in glioblastoma (GBM) and GBM cell lines, meanwhile, its overexpression could markedly reduce cell proliferation, migration, and invasion of glioma cells, implying that it was related with glioblastoma progression. In addition, the overall survival of patient with glioblastoma had a negative correlation with the MX2 expression. Then, Western blot indicated the potential mechanism of MX2 in glioblastoma. We found that MX2 overexpression could decrease the relative levels of phosphorylated-ERK1/2 (p-ERK1/2), p-p38, and nuclear factor-κB (NF-κB), while have no effects on extracellular signal-regulated kinase (ERK), p38, and lamin B1. Moreover, the influences of MX2 overexpression on cell proliferation, migration, and invasion could be weakened by the three inhibitors (PD98059, SB203580, and (pyridin-2-ylmethyl) dithiocarbamate [PDTC]). These results implied that MX2 might suppress the proliferation and metastasis of glioma cells by manipulating the ERK/P38/NF-κB signaling pathway. In conclusion, MX2 is potential to be a new marker used for glioblastoma prognosis or a new target for glioblastoma treatments. 10.1002/jcb.29189