TFEB Supports Pancreatic Cancer Growth through the Transcriptional Regulation of Glutaminase

Simple Summary Pancreatic cancer is a highly lethal tumor with poor prognosis. In general, pancreatic cancer is not detected in its early stages since there are no signs or symptoms. A surgical resection gives the best chance for a cure, but these lesions are detected at the terminal or metastatic stages in most patients and surgery is therefore no longer feasible. New therapeutic options are thus necessary for the pancreatic cancer treatment. Alterations to metabolic pathways have recently attracted great interest as possible cancer treatments and many studies have reported that targeting glutaminase is an ideal approach in many cancers. Here, we provide reliable evidence that pancreatic cancer requires TFEB for maintaining glutaminase-mediated glutamine metabolism, and that this is an attractive new target for pancreatic cancer therapy. Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, we show that pancreatic cancer cells exhibit a significantly elevated TFEB expression compared with normal tissue samples and that the genetic inhibition of TFEB results in a significant inhibition in both glutamine and mitochondrial metabolism, which in turn suppresses the PDAC growth both in vitro and in vivo. High basal levels of autophagy are critical for pancreatic cancer growth. The TFEB knockdown had no significant effect on the autophagic flux under normal conditions but interestingly caused a profound reduction in glutaminase (GLS) transcription, leading to an inhibition of glutamine metabolism. We observed that the direct binding of TFEB to the GLS and TFEB gene promotors regulates the transcription of GLS. We also found that the glutamate supplementation leads to a significant recovery of the PDAC growth that had been reduced by a TFEB knockdown. Taken together, our current data demonstrate that TFEB supports the PDAC cell growth by regulating glutaminase-mediated glutamine metabolism.

Automated summary

Pancreatic cancer is a deadly tumor with poor prognosis, often detected in advanced stages. TFEB expression in pancreatic cancer cells plays a crucial role in regulating glutaminase-mediated glutamine metabolism, suggesting it as a potential new target for therapy.