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ATF3 and JDP2 deficiency in cancer associated fibroblasts promotes tumor growth via SDF-1 transcription.

ABSTRACT: The activating transcription factor 3 (ATF3) and the c-Jun dimerization protein 2 (JDP2) are members of the basic leucine zipper (bZIP) family of transcription factors. These proteins share a high degree of homology and both can activate or repress transcription. Deficiency of either one of them in the non-cancer host cells was shown to reduce metastases. As ATF3 and JDP2 compensate each other's function, we studied the double deficiency of ATF3 and JDP2 in the stromal tumor microenvironment. Here, we show that mice with ATF3 and JDP2 double deficiency (designated thereafter dKO) developed larger tumors with high vascular perfusion and increased cell proliferation rate compared to wild type (WT) mice. We further identify that the underlying mechanism involves tumor associated fibroblasts which secrete high levels of stromal cell-derived factor 1 (SDF-1) in dKO fibroblasts. SDF-1 depletion in dKO fibroblasts dampened tumor growth and blood vessel perfusion. Furthermore, ATF3 and JDP2 were found to regulate SDF-1 transcription and secretion in fibroblasts, a phenomenon that is potentiated in the presence of cancer cells. Collectively, our results suggest that ATF3 and JDP2 regulate the expression of essential tumor promoting factors expressed by fibroblasts within the tumor microenvironment, and thus restrain tumor growth.

SUBMITTER: Avraham S

PROVIDER: S-EPMC6756089 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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ATF3 and JDP2 deficiency in cancer associated fibroblasts promotes tumor growth via SDF-1 transcription.

Avraham Shimrit S Korin Ben B Aviram Sharon S Shechter Dvir D Shaked Yuval Y Aronheim Ami A

Oncogene 20190122 20

The activating transcription factor 3 (ATF3) and the c-Jun dimerization protein 2 (JDP2) are members of the basic leucine zipper (bZIP) family of transcription factors. These proteins share a high degree of homology and both can activate or repress transcription. Deficiency of either one of them in the non-cancer host cells was shown to reduce metastases. As ATF3 and JDP2 compensate each other's function, we studied the double deficiency of ATF3 and JDP2 in the stromal tumor microenvironment. He ...[more]

PMID: 30670778

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Project description:Background: The transcription factor EVI1 regulates cellular proliferation, differentiation, and apoptosis, and contributes to an aggressive course of disease in myeloid leukemias and other malignancies. Notwithstanding, knowledge about the target genes mediating its biological and pathological functions remains limited. We therefore aimed to identify and characterize novel EVI1 target genes in human myeloid cells. Methods: U937T_EVI1, a previously established human myeloid cell line expressing EVI1 in a tetracycline regulable manner, was subjected to genome wide gene expression microarray analysis. qRT-PCR was used to confirm the regulation of MS4A3 by EVI1. Reporter constructs containing various parts of the MS4A3 upstream region were employed in luciferase assays, and direct binding of EVI1 to the MS4A3 promoter was investigated by chromatin immunoprecipitation. U937 derivative cell lines experimentally expressing EVI1 and/or MS4A3 were generated by retroviral transduction, and tested for their tumorigenicity by subcutaneous injection into severe combined immunodeficient mice. Experimental results were tested for statistical significance using ANOVA and Student's t-test (two-tailed). Results: Gene expression microarray analysis identified 27 unique genes that were up-regulated and 29 that were down-regulated in response to EVI1 induction in the human myeloid cell line, U937. The most strongly repressed gene was membrane-spanning-4-domains subfamily-A member-3 (MS4A3), and its down-regulation by EVI1 was confirmed by qRT-PCR in additional, independent experimental model systems. Reporter gene assays and chromatin immunoprecipitation showed that EVI1 regulated MS4A3 via direct binding to a promoter proximal region. Experimental re-expression of MS4A3 in an EVI1 overexpressing cell line counteracted the tumor promoting effect of EVI1 in a murine xenograft model. Conclusions: Our data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness. Time course of 2 biological replicates, plus 2 control samples; 20 arrays in total

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ATF3 and JDP2 deficiency in cancer associated fibroblasts promotes tumor growth via SDF-1 transcription.

Publications

ATF3 and JDP2 deficiency in cancer associated fibroblasts promotes tumor growth via SDF-1 transcription.

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