c-Fos regulated by TMPO/ERK axis promotes 5-FU resistance via inducing NANOG transcription in colon cancer,Cell Death & Disease

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c-Fos regulated by TMPO/ERK axis promotes 5-FU resistance via inducing NANOG transcription in colon cancer
Cell Death & Disease ( IF 8.1 ) Pub Date : 2024-01-17 , DOI: 10.1038/s41419-024-06451-w
Yanping Gui ₁ , Xiaoping Qian ₂ , Youxiang Ding ₃ , Qianqian Chen ₁ , Fangyu Ye ₁ , Yuting Ye ₁ , Yingjian Hou ₁ , Jun Yu ₄ , Li Zhao ₁

Affiliation

AbstractAcquired drug resistance is one of the most common limitations for the clinical response of colon cancer to 5-Fluorouracil (5-FU)-based chemotherapy. The relevant molecular mechanisms might be diversity, but still not be elucidated clearly. In this study, we aimed to investigate the potential mechanisms of c-Fos, a subfamily of activator protein-1, in 5-FU chemoresistance. We determined that phosphorylated c-Fos promoted colon cancer cells resistance to 5-FU by facilitating the cancer stemness. Mechanically, 5-FU treatment induced autolysosome-dependent degradation of TMPO, which subsequently triggered ERK-mediated phosphorylation of c-Fos. Additionally, c-Fos was found to bind to the promoter of NANOG and phosphorylation of c-Fos at Ser 374 was required for its regulation of NANOG expression. NANOG ablation impaired c-Fos/p-c-Fos induced 5-FU resistance and stemness. Taken together, these findings revealed that TMPO-mediated phosphorylation of c-Fos conferred 5-FU resistance by regulating NANOG expression and promoting cell stemness in colon cancer cells. c-Fos could be as a therapeutic target for colon cancer.

中文翻译：

TMPO/ERK 轴调节的 c-Fos 通过诱导结肠癌中的 NANOG 转录促进 5-FU 耐药

摘要获得性耐药是结肠癌对基于 5-氟尿嘧啶 (5-FU) 的化疗的临床反应的最常见限制之一。相关的分子机制可能多种多样，但仍未明确阐明。在本研究中，我们旨在研究激活蛋白 1 的一个亚家族 c-Fos 在 5-FU 化疗耐药中的潜在机制。我们确定磷酸化的 c-Fos 通过促进癌症干细胞性来促进结肠癌细胞对 5-FU 的抵抗。从机械角度来看，5-FU 处理诱导 TMPO 的自溶酶体依赖性降解，随后触发 ERK 介导的 c-Fos 磷酸化。此外，发现 c-Fos 与 NANOG 的启动子结合，并且 c-Fos 在 Ser 374 处的磷酸化是其调节 NANOG 表达所必需的。 NANOG 消融损害了 c-Fos/pc-Fos 诱导的 5-FU 耐药性和干性。总而言之，这些发现表明，TMPO 介导的 c-Fos 磷酸化通过调节 NANOG 表达并促进结肠癌细胞的细胞干性而赋予 5-FU 耐药性。 c-Fos 可以作为结肠癌的治疗靶点。

更新日期：2024-01-17

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