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Fucosyltransferase 8 regulation and breast cancer suppression by transcription factor activator protein 2γ.

ABSTRACT: Alterations of glycosyltransferase expression are often associated with tumor occurrence and progression. Among the many glycosyltransferases, increased expression of fucosyltransferase 8 (FUT8) has been frequently observed to be involved in progression and metastasis of various types of cancer. The regulatory mechanisms of FUT8 expression remain unclear. FUT8 expression was shown, in this study, to be elevated in breast cancer. Systematic analysis revealed that transcription factor activator protein 2γ (AP-2γ) is the target gene of microRNA-10b (miR-10b), which we previously identified as a positive regulator of FUT8. Overexpression of AP-2γ inhibited FUT8 expression, with associated reduction of cell invasiveness and migration ability. AP-2γ was capable of binding to transcription factor STAT3, and phosphorylation of STAT3 induced transcription of the FUT8 gene. On the basis of our findings, we propose that binding of AP-2γ to STAT3 results in formation of the AP-2γ/STAT3 complex and consequent inhibition of STAT3 phosphorylation, thereby preventing entry of p-STAT3 into the nucleus to initiate FUT8 transcription. This study clarifies the molecular mechanisms whereby transcription factor AP-2γ regulates FUT8 expression in breast cancer.

SUBMITTER: Ma M

PROVIDER: S-EPMC8353918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Maspin is a tumor and metastasis suppressor playing an essential role as gatekeeper of tumor progression. It is highly expressed in epithelial cells but is silenced in the onset of metastatic disease by epigenetic mechanisms. Reprogramming of Maspin epigenetic silencing offers a therapeutic potential to lock metastatic progression. Herein we have investigated the ability of the Artificial Transcription Factor 126 (ATF-126) designed to upregulate the Maspin promoter to inhibit tumor progression in pre-established breast tumors in immunodeficient mice. ATF-126 was transduced in the aggressive, mesenchymal-like and triple negative breast cancer line, MDA-MB-231. Induction of ATF expression in vivo by Doxycycline resulted in 50% reduction in tumor growth and totally abolished tumor cell colonization. Genome-wide transcriptional profiles of ATF-induced cells revealed a gene signature that was found over-represented in estrogen receptor positive (ER+) "Normal-like" intrinsic subtype of breast cancer and in poorly aggressive, ER+ luminal A breast cancer cell lines. The comparison transcriptional profiles of ATF-126 and Maspin cDNA defined an overlapping 19-gene signature, comprising novel targets downstream the Maspin signaling cascade. Our data suggest that Maspin up-regulates downstream tumor and metastasis suppressor genes that are silenced in breast cancers, and are normally expressed in the neural system, including CARNS1, SLC8A2 and DACT3. In addition, ATF-126 and Maspin cDNA induction led to the re-activation of tumor suppressive miRNAs also expressed in neural cells, such as miR-1 and miR-34, and to the down-regulation of potential oncogenic miRNAs, such as miR-10b, miR-124, and miR-363. As expected from its over-representation in ER+ tumors, the ATF-126-gene signature predicted favorable prognosis for breast cancer patients. Our results describe for the first time an ATF able to reduce tumor growth and metastatic colonization by epigenetic reactivation of a dormant, normal-like, and more differentiated gene program.

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Fucosyltransferase 8 regulation and breast cancer suppression by transcription factor activator protein 2γ.

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