A Novel KLF4/LDHA Signaling Pathway Regulates Aerobic Glycolysis in and Progression of Pancreatic Cancer

• Published in: Clinical cancer research Vol. 20; no. 16; pp. 4370 - 4380
• Main Authors: Shi, Min, Cui, Jiujie, Du, Jiawei, Wei, Daoyan, Jia, Zhiliang, Zhang, Jun, Zhu, Zhenggang, Gao, Yong, Xie, Keping
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-08-2014
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Chromatin Immunoprecipitation; Disease Progression; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Glucose - metabolism; Glycolysis; Humans; Immunoenzyme Techniques; Isoenzymes - genetics; Isoenzymes - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Pancreas - metabolism; Pancreas - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmacology. Drug treatments; Prognosis; Promoter Regions, Genetic - genetics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Cells, Cultured; Tumors; Signal transduction; Signaling pathway; Pancreas cancer; Glycolysis; Digestive diseases; Malignant tumor; Krppel-like factor 4; Cancer; Pancreatic disease
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-14-0186

Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effect on aerobic glycolysis in pancreatic tumors. Therefore, we investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling in aerobic glycolysis in pancreatic cancer cells.
Expression of KLF4 and lactate dehydrogenase A (LDHA) in 70 primary pancreatic tumors and 10 normal pancreatic tissue specimens was measured. Also, the underlying mechanisms of altered KLF4 expression and its impact on aerobic glycolysis in pancreatic cancer cells were investigated.
We found a negative correlation between KLF4 and LDHA expression in pancreatic cancer cells and tissues and that their expression was associated with clinicopathologic features of pancreatic cancer. KLF4 underexpression and LDHA overexpression were correlated with disease stage and tumor differentiation. Experimentally, KLF4 overexpression significantly attenuated the aerobic glycolysis in and growth of pancreatic cancer cells both in vitro and in orthotopic mouse models, whereas knockdown of KLF4 expression had the opposite effect. Enforced KLF4 expression decreased LDHA expression, whereas small interfering RNA-mediated knockdown of KLF4 expression had the opposite effect. Mechanistically, KLF4 bound directly to the promoter regions of the LDHA gene and negatively regulated its transcription activity.
Dysregulated signaling in this novel KLF4/LDHA pathway significantly impacts aerobic glycolysis in and development and progression of pancreatic cancer.