Kim Ji Hye, Lee Jinyoung, Cho Young-Ra, Lee So-Yeon, Sung Gi-Jun, Shin Dong-Myung, Choi Kyung-Chul, Son Jaekyoung
Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul 05505, Korea.
Cancers (Basel). 2021 Jan 27;13(3):483. doi: 10.3390/cancers13030483.
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.
转录因子EB（TFEB）是溶酶体功能和自噬的主要调节因子。此外，TFEB还具有多种生理作用，如营养感知、细胞应激反应和免疫反应。然而，TFEB在胰腺癌生长中的具体作用仍不清楚。在这里，我们表明，与正常组织样本相比，胰腺癌细胞的TFEB表达显著升高，并且TFEB的基因抑制导致谷氨酰胺和线粒体代谢均受到显著抑制，进而在体外和体内均抑制胰腺癌的生长。高水平的基础自噬对胰腺癌的生长至关重要。TFEB敲低在正常条件下对自噬通量没有显著影响，但有趣的是导致谷氨酰胺酶（GLS）转录大幅减少，从而抑制谷氨酰胺代谢。我们观察到TFEB与GLS和TFEB基因启动子的直接结合调节GLS的转录。我们还发现，补充谷氨酸可显著恢复因TFEB敲低而降低的胰腺癌生长。综上所述，我们目前的数据表明，TFEB通过调节谷氨酰胺酶介导的谷氨酰胺代谢来支持胰腺癌细胞的生长。
