GAS41 通过 H2A.Z.2 和 Notch1 介导胰腺癌的增殖和 GEM 化疗耐药性。
GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer.
机构信息
Department of Intervention and Vascular Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 50 Chifeng Road, Yangpu, Shanghai, 200072, China.
National Center Clinical Research for Interventional Medicine, Shanghai Tenth People's Hospital, 50 Chifeng Road, Yangpu, Shanghai, 200072, China.
出版信息
Cell Oncol (Dordr). 2022 Jun;45(3):429-446. doi: 10.1007/s13402-022-00675-8. Epub 2022 May 3.
PURPOSE
GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role.
METHODS
GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer.
RESULTS
We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM.
CONCLUSION
Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.
目的
GAS41 是一个 YEATS 结构域蛋白，它与乙酰化组蛋白 H3 结合，促进非小细胞肺癌中 H2A.Z 的染色质沉积。GAS41 在胰腺癌中的作用尚不清楚。本研究旨在揭示其作用。
方法
采用 qRT-PCR、Western blot 和免疫组化检测胰腺癌组织和细胞系中 GAS41 的表达。采用 MTT、集落形成、球体形成和体内肿瘤生成实验评估胰腺癌细胞的增殖、肿瘤发生、干性和吉西他滨（GEM）耐药性。通过共免疫沉淀（co-IP）和染色质免疫沉淀（ChIP）实验评估 GAS41、H2A.Z.2 和 Notch1 在胰腺癌中的作用机制。
结果
我们发现 GAS41 在人胰腺癌组织和细胞系中过度表达，并且在获得 GEM 耐药性后其表达增加。我们还发现 GAS41 上调 Notch 以及胰腺癌细胞干性和体外及体内 GEM 耐药性。我们表明 GAS41 与 H2A.Z.2 结合并激活 Notch 及其下游介质，从而调节干性和耐药性。GAS41 或 H2A.Z.2 的耗竭会下调 Notch 并使胰腺癌细胞对 GEM 敏感。
结论
我们的数据表明，GAS41 通过 H2A.Z.2 和 Notch1 介导胰腺癌细胞的增殖和 GEM 耐药性。
Zotero 插件