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SAA1 is upregulated in gastric cancer-associated fibroblasts possibly by its enhancer activation.

Carcinogenesis (2020-12-08)
Yoshimi Yasukawa, Naoko Hattori, Naoko Iida, Hideyuki Takeshima, Masahiro Maeda, Tohru Kiyono, Shigeki Sekine, Yasuyuki Seto, Toshikazu Ushijima
RÉSUMÉ

Cancer-associated fibroblasts (CAFs) tend to have tumor-promoting capacity, and can provide therapeutic targets. Even without cancer cells, CAF phenotypes are stably maintained, and DNA methylation and H3K27me3 changes have been shown to be involved. Here, we searched for a potential therapeutic target in primary CAFs from gastric cancer and a mechanism for its dysregulation. Expression microarray using eight CAFs and seven non-CAFs (NCAFs) revealed that serum amyloid A1 (SAA1), which encodes an acute phase secreted protein, was second most upregulated in CAFs, following IGF2. Conditioned medium (CM) derived from SAA1-overexpressing NCAFs was shown to increase migration of gastric cancer cells compared with that from control NCAFs, and its tumor-promoting effect was comparable to that of CM from CAFs. In addition, increased migration of cancer cells by CM from CAFs was mostly canceled with CM from CAFs with SAA1 knockdown. Chromatin immunoprecipitation (ChIP)-quantitative PCR showed that CAFs had higher levels of H3K27ac, an active enhancer mark, in the promoter and the two far upstream regions of SAA1 than NCAFs. Also, BET bromodomain inhibitors, JQ1 and mivebresib, decreased SAA1 expression and tumor-promoting effects in CAFs, suggesting SAA1 upregulation by enhancer activation in CAFs. Our present data showed that SAA1 is a candidate therapeutic target from gastric CAFs and indicated that increased enhancer acetylation is important for its overexpression.

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Anticorps anti-triméthyl-histone H3 (Lys27), Upstate®, from rabbit
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ChIPAb+ MED1 Antibody - ChIP Validated Antibody and Primer Set, from rabbit, purified by affinity chromatography