Loss of GATA6-mediated up-regulation of UTX promotes pancreatic tumorigenesis and progression

Hui-Qing Zhang; Fanyang Kong; Xiangyu Kong; Tingting Jiang; Muyuan Ma; Shaojiang Zheng; Junli Guo; Keping Xie

doi:10.1016/j.gendis.2023.01.019

Loss of GATA6-mediated up-regulation of UTX promotes pancreatic tumorigenesis and progression

Genes Dis. 2023 Mar 31;11(2):921-934. doi: 10.1016/j.gendis.2023.01.019. eCollection 2024 Mar.

Authors

Hui-Qing Zhang¹, Fanyang Kong², Xiangyu Kong², Tingting Jiang³, Muyuan Ma³, Shaojiang Zheng⁴, Junli Guo⁵, Keping Xie³

Affiliations

¹ The Third Department of Medical Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330006, China.
² Departments of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
³ Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China.
⁴ Hainan Clinical Medical Research Center of the First Affiliated Hospital, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, Hainan 570102, China.
⁵ Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, Hainan 571199, China.

Abstract

Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), also known as lysine (K)-specific demethylase 6A (KDM6A), functions as a tumor suppressor gene or oncogene depending on the tumor type and context. However, its tumor-suppressive mechanisms remain largely unknown. Here, we investigated the clinical significance and biological effects of UTX expression in pancreatic ductal adenocarcinoma (PDA) and determined the potential mechanisms of its dysregulation. UTX expression and its association with clinicopathologic characteristics of PDA patients were analyzed using immunohistochemistry. UTX mRNA and protein expression and their regulation in PDA cell lines were measured using quantitative polymerase chain reaction and Western blot analyses. The biological functions of UTX in PDA cell growth, migration, and invasion were determined using gain- and loss-of-function assays with both in vitro and in vivo animal models. UTX expression was reduced in human PDA cell lines and specimens. Low UTX expression was associated with poor differentiation and prognosis in PDA. Forced UTX expression inhibited PDA proliferation, migration, and invasion in vitro and PDA growth and metastasis in vivo, whereas knockdown of UTX expression did the opposite. Mechanistically, UTX expression was trans-activated by GATA6 activation. GATA6-mediated PDA progression could be blocked, at least partially, by silencing UTX expression. In conclusion, loss of GATA6-mediated UTX expression was evident in human PDA and restored UTX expression suppressed PDA growth and metastasis. Thus, UTX is a tumor suppressor in PDA and may serve as a prognostic biomarker and therapeutic target.

Keywords: Growth; Invasion; Metastasis; Pancreatic cancer; UTX.