Targeting BET Proteins Decreases Hyaluronidase-1 in Pancreatic Cancer.
Targeting BET Proteins Decreases Hyaluronidase-1 in Pancreatic Cancer.
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DOI：
10.3390/cells12111490
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发表时间：
2023-05-27
期刊：
影响因子：
6
通讯作者：
Munshi, Hidayatullah G.
中科院分区：
文献类型：
--
作者：
Kumar, Krishan;Kanojia, Deepak;Bentrem, David J.;Hwang, Rosa F.;Butchar, Jonathan P.;Tridandapani, Susheela;Munshi, Hidayatullah G.
关键词：
背景：胰腺导管腺癌 (PDAC) 的特点是存在富含透明质酸 (HA) 的致密基质，HA 水平升高与更具侵袭性的疾病相关。 HA 降解酶透明质酸酶 (HYAL) 水平的升高也与肿瘤进展相关。在本研究中，我们评估了 PDAC 中 HYAL 的调节作用。方法：使用 siRNA 和小分子抑制剂，我们通过定量实时 PCR (qRT-PCR)、蛋白质印迹分析和 ELISA 评估了 HYAL 的调节作用。通过染色质免疫沉淀 (ChIP) 测定评估 BRD2 蛋白在 HYAL1 启动子上的结合。通过WST-1测定评估增殖。患有异种移植肿瘤的小鼠接受 BET 抑制剂治疗。通过免疫组织化学和 qRT-PCR 分析肿瘤中 HYAL 的表达。结果：我们发现 HYAL1、HYAL2 和 HYAL3 在 PDAC 肿瘤以及 PDAC 和胰腺星状细胞系中表达。我们证明，针对溴结构域和额外末端结构域 (BET) 蛋白（组蛋白乙酰化标记的读取器）的抑制剂主要会降低 HYAL1 的表达。我们发现 BET 家族蛋白 BRD2 通过与其启动子区域结合来调节 HYAL1 表达，并且 HYAL1 下调会减少 PDAC 和星状细胞系的增殖并增强其凋亡。值得注意的是，BET 抑制剂降低体内 HYAL1 表达水平，而不影响 HYAL2 或 HYAL3 水平。结论：我们的结果证明了 HYAL1 的促肿瘤作用，并确定了 BRD2 在 PDAC 中 HYAL1 调节中的作用。总体而言，这些数据增强了我们对 HYAL1 的作用和调节的理解，并为 PDAC 中靶向 HYAL1 提供了理论基础。
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of dense stroma that is enriched in hyaluronan (HA), with increased HA levels associated with more aggressive disease. Increased levels of the HA-degrading enzymes hyaluronidases (HYALs) are also associated with tumor progression. In this study, we evaluate the regulation of HYALs in PDAC. Methods: Using siRNA and small molecule inhibitors, we evaluated the regulation of HYALs using quantitative real-time PCR (qRT-PCR), Western blot analysis, and ELISA. The binding of BRD2 protein on the HYAL1 promoter was evaluated by chromatin immunoprecipitation (ChIP) assay. Proliferation was evaluated by WST-1 assay. Mice with xenograft tumors were treated with BET inhibitors. The expression of HYALs in tumors was analyzed by immunohistochemistry and by qRT-PCR. Results: We show that HYAL1, HYAL2, and HYAL3 are expressed in PDAC tumors and in PDAC and pancreatic stellate cell lines. We demonstrate that inhibitors targeting bromodomain and extra-terminal domain (BET) proteins, which are readers of histone acetylation marks, primarily decrease HYAL1 expression. We show that the BET family protein BRD2 regulates HYAL1 expression by binding to its promoter region and that HYAL1 downregulation decreases proliferation and enhances apoptosis of PDAC and stellate cell lines. Notably, BET inhibitors decrease the levels of HYAL1 expression in vivo without affecting the levels of HYAL2 or HYAL3. Conclusions: Our results demonstrate the pro-tumorigenic role of HYAL1 and identify the role of BRD2 in the regulation of HYAL1 in PDAC. Overall, these data enhance our understanding of the role and regulation of HYAL1 and provide the rationale for targeting HYAL1 in PDAC.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
影响因子：
4.6
作者：
Kumar K;Raza SS;Knab LM;Chow CR;Kwok B;Bentrem DJ;Popovic R;Ebine K;Licht JD;Munshi HG
通讯作者：
Munshi HG
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
29.4
作者：
DuFort CC;DelGiorno KE;Hingorani SR
通讯作者：
Hingorani SR
影响因子：
4.8
作者：
de Sa, Paula Mota;Richard, Allison J.;Stephens, Jacqueline M.
通讯作者：
Stephens, Jacqueline M.