PRRX1 isoforms cooperate with FOXM1 to regulate the DNA damage response in pancreatic cancer cells.,Oncogene

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PRRX1 isoforms cooperate with FOXM1 to regulate the DNA damage response in pancreatic cancer cells.
Oncogene ( IF 6.9 ) Pub Date : 2019-01-31 , DOI: 10.1038/s41388-019-0725-6
Benoît Marchand _{1,

2} , Jason R Pitarresi _{1,

2} , Maximilian Reichert _{1,

3,

4} , Kensuke Suzuki _{1,

2} , Dorottya Laczkó _{1,

2} , Anil K Rustgi _{1,

2,

4}

Affiliation

PRRX1 is a homeodomain transcriptional factor, which has two isoforms, PRXX1A and PRRX1B. The PRRX1 isoforms have been demonstrated to be important in pancreatic cancer, especially in the regulation of epithelial-to-mesenchymal transition (EMT) in Pancreatic Ductal Adenocarcinoma (PDAC) and of mesenchymal-to-epithelial transition (MET) in liver metastasis. In order to determine the functional underpinnings of PRRX1 and its isoforms, we have unraveled a new interplay between PRRX1 and the FOXM1 transcriptional factors. Our detailed biochemical analysis reveals the direct physical interaction between PRRX1 and FOXM1 proteins that requires the PRRX1A/B 200-222/217 amino acid (aa) region and the FOXM1 Forkhead domain. Additionally, we demonstrate the cooperation between PRRX1 and FOXM1 in the regulation of FOXM1-dependent transcriptional activity. Moreover, we establish FOXM1 as a critical downstream target of PRRX1 in pancreatic cancer cells. We demonstrate a novel role for PRRX1 in the regulation of genes involved in DNA repair pathways. Indeed, we show that expression of PRRX1 isoforms may limit the induction of DNA damage in pancreatic cancer cells. Finally, we demonstrate that targeting FOXM1 with the small molecule inhibitor FDI6 suppress pancreatic cancer cell proliferation and induces their apoptotic cell death. FDI6 sensitizes pancreatic cancer cells to Etoposide and Gemcitabine induced apoptosis. Our data provide new insights into PRRX1's involvement in regulating DNA damage and provide evidence of a possible PRRX1-FOXM1 axis that is critical for PDAC cells.

中文翻译：

PRRX1 亚型与 FOXM1 协同调节胰腺癌细胞中的 DNA 损伤反应。

PRRX1 是同源域转录因子，有两种亚型：PRXX1A 和 PRRX1B。 PRRX1 亚型已被证明在胰腺癌中很重要，特别是在调节胰腺导管腺癌 (PDAC) 中的上皮-间质转化 (EMT) 和肝转移中的间质-上皮转化 (MET) 中。为了确定 PRRX1 及其亚型的功能基础，我们揭示了 PRRX1 和 FOXM1 转录因子之间新的相互作用。我们详细的生化分析揭示了 PRRX1 和 FOXM1 蛋白之间的直接物理相互作用，需要 PRRX1A/B 200-222/217 氨基酸 (aa) 区域和 FOXM1 Forkhead 结构域。此外，我们还证明了 PRRX1 和 FOXM1 在 FOXM1 依赖性转录活性调节中的合作。此外，我们将 FOXM1 确定为胰腺癌细胞中 PRRX1 的关键下游靶标。我们证明了 PRRX1 在 DNA 修复途径相关基因调控中的新作用。事实上，我们表明 PRRX1 同工型的表达可能会限制胰腺癌细胞中 DNA 损伤的诱导。最后，我们证明用小分子抑制剂 FDI6 靶向 FOXM1 可抑制胰腺癌细胞增殖并诱导其凋亡细胞死亡。 FDI6 使胰腺癌细胞对依托泊苷和吉西他滨诱导的细胞凋亡敏感。我们的数据为 PRRX1 参与调节 DNA 损伤提供了新的见解，并提供了可能对 PDAC 细胞至关重要的 PRRX1-FOXM1 轴的证据。

更新日期：2019-01-31

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