Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Cell Biology and Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Genes Dev. 2020 Oct 1;34(19-20):1345-1358. doi: 10.1101/gad.340661.120. Epub 2020 Sep 10.
The uptake of macromolecules and cellular debris through macropinocytosis has emerged as an important nutrient acquisition strategy of cancer cells. Genetic alterations commonly found in human cancers (e.g. mutations in or loss of have been shown to increase macropinocytosis. To identify additional effectors that enable cell growth dependent on the uptake of extracellular proteins, pancreatic ductal adenocarcinoma (PDA) cells were selected for growth in medium where extracellular albumin was the obligate source of the essential amino acid leucine. Analysis of global changes in chromatin availability and gene expression revealed that PDA cells selected under these conditions exhibited elevated activity of the transcriptional activators Yap/Taz. Knockout of Yap/Taz prevented growth of PDA cells in leucine-deficient medium, but not in complete medium. Furthermore, constitutively active forms of Yap or Taz were sufficient to stimulate macropinocytosis of extracellular protein. In addition to promoting the uptake of plasma proteins, Yap/Taz also promoted the scavenging of apoptotic cell bodies and necrotic debris by PDA cells. The Yap/Taz transcriptional target was found to be essential for cell growth dependent on the uptake of dead cells and cell debris. Together, these studies suggest that the Hippo pathway effectors Yap and Taz are important transcriptional regulators of endocytic nutrient uptake.
通过巨胞饮作用摄取大分子和细胞碎片已成为癌细胞获取营养的重要策略。在人类癌症中经常发现的遗传改变(例如 或 的突变)已被证明会增加巨胞饮作用。为了确定其他能够使细胞生长依赖于细胞外蛋白质摄取的效应物,选择胰腺导管腺癌(PDA)细胞在培养基中生长,其中细胞外白蛋白是必需氨基酸亮氨酸的必需来源。对染色质可及性和基因表达的全局变化的分析表明,在这些条件下选择的 PDA 细胞表现出转录激活因子 yap/Taz 的活性升高。yap/Taz 的敲除阻止了 PDA 细胞在缺乏亮氨酸的培养基中的生长,但在完全培养基中则不会。此外,yap 或 Taz 的组成性活性形式足以刺激细胞外蛋白质的巨胞饮作用。yap/Taz 除了促进血浆蛋白的摄取外,还促进了 PDA 细胞对凋亡细胞体和坏死碎片的清除。发现 Yap/Taz 的转录靶标 对于依赖摄取死亡细胞和细胞碎片的细胞生长是必需的。总之,这些研究表明 Hippo 通路效应物 yap 和 Taz 是内吞营养摄取的重要转录调节剂。