N6-methyladenosine (m6A) is the most prevalent RNA modification and is associated with various biological processes. Proteins that function as readers and writers of m6A modifications have been shown to play critical roles in human malignancies. Here, we identified KH-type splicing regulatory protein (KHSRP) as an m6A binding protein that contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). High KHSRP levels were detected in PDAC and predicted poor patient survival. KHSRP deficiency suppressed PDAC growth and metastasis in vivo. Mechanistically, KHSRP recognized and stabilized FAK pathway mRNAs, including MET, ITGAV and ITGB1, in an m6A-dependent manner, which led to activation of downstream FAK signaling that promoted PDAC progression. Targeting KHSRP with a PROTAC showed promising tumor suppressive effects in mouse models, leading to prolonged survival. Together, these findings indicate that KHSRP mediates FAK pathway activation in an m6A-dependent manner to support PDAC growth and metastasis, highlighting the potential of KHSRP as a therapeutic target in pancreatic cancer.

中文翻译：

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KHSRP 稳定 m6A 修饰的转录本以激活 FAK 信号传导并促进胰腺导管腺癌进展


N6-甲基腺苷 （m6A） 是最普遍的 RNA 修饰，与各种生物过程有关。作为 m6A 修饰的读取器和写入器的蛋白质已被证明在人类恶性肿瘤中起关键作用。在这里，我们确定 KH 型剪接调节蛋白 （KHSRP） 是一种 m6A 结合蛋白，有助于胰腺导管腺癌 （PDAC） 的进展。在 PDAC 中检测到高 KHSRP 水平，预测患者生存率差。KHSRP 缺陷抑制体内 PDAC 生长和转移。从机制上讲，KHSRP 以 m6A 依赖性方式识别并稳定 FAK 通路 mRNA，包括 MET 、 ITGAV 和 ITGB1，这导致下游 FAK 信号转导的激活，从而促进 PDAC 进展。用 PROTAC 靶向 KHSRP 在小鼠模型中显示出有希望的肿瘤抑制作用，从而延长生存期。总之，这些发现表明 KHSRP 以 m6A 依赖性方式介导 FAK 通路激活以支持 PDAC 生长和转移，突出了 KHSRP 作为胰腺癌治疗靶点的潜力。