Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, PR China.
Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, PR China.
Pancreatology. 2023 Sep;23(6):630-641. doi: 10.1016/j.pan.2023.06.011. Epub 2023 Jul 7.
Pancreatic cancer is a common digestive system cancer and one of the most lethal malignancies worldwide. Ataxin-3 (ATXN3) protein is a deubiquitinating enzyme implicated in the occurrence of diverse human cancers. The potential role of ATXN3 in pancreatic cancer still remains unclear.
ATXN3 was screened from differentially-upregulated genes of GSE71989, GSE27890 and GSE40098 datasets. The mRNA and protein levels of ATXN3 was evaluated in pancreatic cancer samples and cell lines. Through the gain- and loss-of-function experiments, the effects of ATXN3 on cell proliferation, migration and invasion were evaluated using cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) staining, wound healing and Transwell assays. Subsequently, the interaction between ATXN3 and HDAC6 was confirmed using double immunofluorescence staining, co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The underlying mechanism of ATXN3 was determined by knockdown of HDAC6 in ATXN3-upregulated pancreatic cancer cells. The function of ATXN3 in vivo was verified through xenograft assay.
High expression of ATXN3 was found in pancreatic cancer tissues. Increased ATXN3 expression dramatically promoted cell proliferation, migration, and invasion. The malignant phenotypes were suppressed in ATXN3-silenced pancreatic cancer cells. ATXN3 was proved to interact with HDAC6 and regulate its degradation through deubiquitination. Downregulation of HDAC6 inhibited ATXN3-induced development of pancreatic cancer cells through regulating the expression of PCNA, vimentin and E-cadherin. ATXN3 facilitated tumor growth of pancreatic cancer and increased HDAC6 expression in vivo.
This study confirmed that ATXN3 facilitated malignant phenotypes of pancreatic cancer via reducing the ubiquitination of HDAC6.
胰腺癌是一种常见的消化系统癌症，也是全球最致命的恶性肿瘤之一。Ataxin-3（ATXN3）蛋白是一种去泛素化酶，与多种人类癌症的发生有关。ATXN3 在胰腺癌中的潜在作用尚不清楚。
从 GSE71989、GSE27890 和 GSE40098 数据集的差异上调基因中筛选 ATXN3。评估 ATXN3 在胰腺癌样本和细胞系中的 mRNA 和蛋白水平。通过 gain-和 loss-of-function 实验，使用细胞计数试剂盒-8（CCK-8）、5-乙炔基-2'-脱氧尿苷（EdU）染色、划痕愈合和 Transwell 测定评估 ATXN3 对细胞增殖、迁移和侵袭的影响。随后，通过双免疫荧光染色、共免疫沉淀（co-IP）和邻近连接分析（PLA）证实 ATXN3 与 HDAC6 之间的相互作用。通过在 ATXN3 上调的胰腺癌细胞中敲低 HDAC6 来确定 ATXN3 的潜在机制。通过异种移植实验验证 ATXN3 在体内的功能。
发现 ATXN3 在胰腺癌组织中高表达。增加 ATXN3 的表达显著促进了细胞的增殖、迁移和侵袭。沉默 ATXN3 的胰腺癌细胞中的恶性表型受到抑制。证明 ATXN3 通过去泛素化调节其降解与 HDAC6 相互作用。下调 HDAC6 通过调节 PCNA、波形蛋白和 E-钙黏蛋白的表达抑制 ATXN3 诱导的胰腺癌细胞的发育。ATXN3 促进胰腺癌肿瘤的生长，并增加体内的 HDAC6 表达。
本研究证实，ATXN3 通过减少 HDAC6 的泛素化促进胰腺癌的恶性表型。
