TY - JOUR
T1 - KLF4-mediated suppression of CD44 signaling negatively impacts pancreatic cancer stemness and metastasis
AU - Yan, Yongmin
AU - Li, Zhiwei
AU - Kong, Xiangyu
AU - Jia, Zhiliang
AU - Zuo, Xiangsheng
AU - Gagea, Mihai
AU - Huang, Suyun
AU - Wei, Daoyan
AU - Xie, Keping
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/4/15
Y1 - 2016/4/15
N2 - KLF4 and CD44 regulate cancer cell stemness, but their precise functions and roles in metastatic progression are not well understood. In this study, we used both inducible and genetic engineering approaches to assess whether the activities of these two factors intersect in pancreatic cancer. We found that genetic ablation of Klf4 in pancreatic cancer cells isolated from Klf4flox/flox mice drastically increased CD44 expression and promoted the acquisition of stem-like properties, whereas tetracycline-inducible expression of KLF4 suppressed these properties in vitro and in vivo. Further mechanistic investigation revealed that KLF4 bound to the CD44 promoter to negatively regulate transcription and also the expression of the CD44 variant. Moreover, in human pancreatic ductal adenocarcinoma (PDAC) tissues, the expression patterns of KLF4 and CD44 were mutually exclusive, and this inverse relationship was particularly striking in human metastatic pancreatic tumors and in autochthonous mouse models of PDAC. Taken together, our findings demonstrate that KLF4 acts as a tumor suppressor in PDAC cells that restricts metastatic behaviors through direct negative regulation of CD44, providing support for the clinical investigation of therapeutic approaches focusing on targeted KLF4 activation in advanced tumors.
AB - KLF4 and CD44 regulate cancer cell stemness, but their precise functions and roles in metastatic progression are not well understood. In this study, we used both inducible and genetic engineering approaches to assess whether the activities of these two factors intersect in pancreatic cancer. We found that genetic ablation of Klf4 in pancreatic cancer cells isolated from Klf4flox/flox mice drastically increased CD44 expression and promoted the acquisition of stem-like properties, whereas tetracycline-inducible expression of KLF4 suppressed these properties in vitro and in vivo. Further mechanistic investigation revealed that KLF4 bound to the CD44 promoter to negatively regulate transcription and also the expression of the CD44 variant. Moreover, in human pancreatic ductal adenocarcinoma (PDAC) tissues, the expression patterns of KLF4 and CD44 were mutually exclusive, and this inverse relationship was particularly striking in human metastatic pancreatic tumors and in autochthonous mouse models of PDAC. Taken together, our findings demonstrate that KLF4 acts as a tumor suppressor in PDAC cells that restricts metastatic behaviors through direct negative regulation of CD44, providing support for the clinical investigation of therapeutic approaches focusing on targeted KLF4 activation in advanced tumors.
UR - http://www.scopus.com/inward/record.url?scp=84970948465&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84970948465&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-1691
DO - 10.1158/0008-5472.CAN-15-1691
M3 - Article
C2 - 26880805
AN - SCOPUS:84970948465
SN - 0008-5472
VL - 76
SP - 2419
EP - 2431
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -