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KLF15 通过降低 USP21 介导的 Nanog 稳定性来抑制胰腺癌的干性。

KLF15 suppresses stemness of pancreatic cancer by decreasing USP21-mediated Nanog stability.

机构信息

Department of Clinical Laboratory, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Hexi District, Huanhuxi Road, Tianjin, 300060, China.

Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.

出版信息

Cell Mol Life Sci. 2024 Oct 5;81(1):417. doi: 10.1007/s00018-024-05442-6.

DOI:10.1007/s00018-024-05442-6
PMID:39367978
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11455850/
Abstract

The existence of cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) is considered to be the key factor for metastasis and chemoresistance. Thus, novel therapeutic strategies for eradicating CSCs are urgently needed. Here we aimed to explore the role of KLF15 in stemness and the feasibility of using KLF15 to inhibit CSCs and improve chemotherapy sensitivity in PDAC. In this study, we report that KLF15 is negatively associated with poor survival and advanced pathological staging of PDAC. Moreover, tumorous KLF15 suppresses the stemness of PDAC by promoting the degradation of Nanog, and KLF15 directly interacts with Nanog, inhibiting interaction between Nanog with USP21. We also demonstrate that the KLF15/Nanog complex inhibit the stemness in vivo and in PDX cells. Tazemetostat suppresses stemness and sensitizes PDAC cells to gemcitabine by promoting KLF15 expression in PDAC. In summary, the findings of our study confirm the value of KLF15 level in diagnosis and prognosis of PDAC, it is the first time to explore the inhibition role of KLF15 in stemness of PDAC and the regulation mechanism of Nanog, contributing to provide a new therapeutic strategy that using Tazemetostat sensitizes PDAC cells to gemcitabine by promoting KLF15 expression for PDAC.

摘要

胰腺癌中癌症干细胞（CSC）的存在被认为是转移和化疗耐药的关键因素。因此，迫切需要新的治疗策略来根除 CSC。在这里，我们旨在探索 KLF15 在干性中的作用，以及使用 KLF15 抑制 CSC 并提高胰腺癌化疗敏感性的可行性。在这项研究中，我们报告 KLF15 与胰腺癌的不良生存和晚期病理分期呈负相关。此外，肿瘤 KLF15 通过促进 Nanog 的降解来抑制胰腺癌的干性，并且 KLF15 直接与 Nanog 相互作用，抑制 Nanog 与 USP21 的相互作用。我们还证明 KLF15/Nanog 复合物在体内和 PDX 细胞中抑制干性。Tazemetostat 通过促进 PDAC 中 KLF15 的表达来抑制干性并使 PDAC 细胞对吉西他滨敏感。总之，我们的研究结果证实了 KLF15 水平在胰腺癌诊断和预后中的价值，这是首次探索 KLF15 在胰腺癌干性中的抑制作用及其对 Nanog 的调控机制，有助于提供一种新的治疗策略，即通过促进 KLF15 的表达使 Tazemetostat 使 PDAC 细胞对吉西他滨敏感，用于治疗胰腺癌。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/84b374f13f01/18_2024_5442_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/6ce6a7fec223/18_2024_5442_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/a212c2052afc/18_2024_5442_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/b76ab38714a9/18_2024_5442_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/23341c9ce6ea/18_2024_5442_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/d1f849a23726/18_2024_5442_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/84b374f13f01/18_2024_5442_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/6ce6a7fec223/18_2024_5442_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/a212c2052afc/18_2024_5442_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/b76ab38714a9/18_2024_5442_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/23341c9ce6ea/18_2024_5442_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/d1f849a23726/18_2024_5442_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b53b/11455850/84b374f13f01/18_2024_5442_Fig6_HTML.jpg

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