ZKSCAN5 activates LAPTM5 expression by recruiting SETD7 to promote metastasis in pancreatic ductal adenocarcinoma
Yong Yang1,2*, Wei Xie3*, Xuan Qiao4, Jun Yang2, Dan Yao5 and Dongming Zhu1
1Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 2Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 3Department of General Surgery, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, 4Graduate School, Xuzhou Medical University, Xuzhou and 5Department of Gastrointestinal Surgery, Huai'an Second People's Hospital, the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, PR China
*Yong Yang and Wei Xie contributed equally to this work
Corresponding Author: Dongming Zhu, Department of General Surgery, The First Affiliated Hospital of Soochow University, No. 188, Shizi Street, Gusu District, Suzhou 215000, Jiangsu, PR China. e-mail: Zhudm_gs913@163.com
Summary. Lysosomal-associated transmembrane protein 5 (LAPTM5) has been associated with poor prognosis in cancer patients. Its role in regulating metastasis in pancreatic ductal adenocarcinoma (PDAC), however, remains vague. The study here aimed to expound the metastasis-promoting properties of LAPTM5 in PDAC and the detailed mechanism. LAPTM5 was overexpressed in metastatic PDAC cells and was related to the dismal prognosis of patients in GEO datasets. By using lentiviral vectors harboring short hairpin RNA, we found that LAPTM5 downregulation reduced PDAC cell viability, proliferation, and aggressiveness in vitro and liver metastasis in vivo. Zinc finger with KRAB and SCAN domains 5 (ZKSCAN5) was predicted and verified to mediate LAPTM5 transcription in PDAC cells. Both ZKSCAN5 and SET domains, containing lysine methyltransferase 7 (SETD7) bound to the LAPTM5 promoter, and ZKSCAN5 recruited SETD7 to form a complex promoting LAPTM5 transcription. LAPTM5 knockdown reversed the promoting effect of ZKSCAN5 on the metastasis of PDAC cells. Thus, our findings on the ZKSCAN5/SETD7/LAPTM5 axis provide insights into the underlying mechanism of liver metastasis dissemination in PDAC. Histol Histopathol 39, 747-760 (2024)
Key words: LAPTM5, ZKSCAN5, Pancreatic ductal adenocarcinoma, SETD7, Liver metastasis
DOI: 10.14670/HH-18-678
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©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License. |
