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.