MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1

Ying Yang, Mari B. Ishak Gabra, Eric A. Hanse, Xazmin H. Lowman, Thai Q. Tran, Haiqing Li, Neta Milman, Juan Liu, Michael A. Reid, Jason W. Locasale, Ziv Gil and Mei Kong ()
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Ying Yang: University of California
Mari B. Ishak Gabra: University of California
Eric A. Hanse: University of California
Xazmin H. Lowman: University of California
Thai Q. Tran: University of California
Haiqing Li: City of Hope
Neta Milman: The Technion-Israel Institute of Technology
Juan Liu: Duke University School of Medicine
Michael A. Reid: Duke University School of Medicine
Jason W. Locasale: Duke University School of Medicine
Ziv Gil: The Technion-Israel Institute of Technology
Mei Kong: University of California

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.

Date: 2019
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DOI: 10.1038/s41467-019-08759-0

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