Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.
Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.
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BMAL2 的 Ras 依赖性激活调节胰腺癌的缺氧代谢。
DOI：
10.1101/2023.03.19.533333
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发表时间：
2023
期刊：
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作者：
Maurer,HCarlo;Curiel-Garcia,Alvaro;Holmstrom,Sam;Laise,Pasquale;Palermo,CarmineF;Sastra,StevenA;Andren,Anthony;Li,Zhang;LeLarge,Tessa;Sagalovskiy,Irina;Ross,DanielR;Rosario,Vilma;Lu,Kate;Ferraiuolo,Ethan;Spinosa,Nicholas;
为了确定人类胰腺导管腺癌（PDAC）中恶性肿瘤的驱动因素，我们对来自PDAC和良性前体的激光捕获显微切割样品的大量表达谱进行了调控网络分析。我们发现BMAL2在PDAC的发生、进展、切除后存活和KRAS活性中起作用。BMAL2靶基因的功能分析使我们假设它在调节对缺氧的反应中起作用，这是PDAC生理学的一个关键但知之甚少的特征。在多种人PDAC细胞系中敲除BMAL2揭示了对活力和侵袭的影响，特别是在缺氧条件下。BMAL2的丢失也影响糖酵解和其他代谢过程。我们发现BMAL2直接调节缺氧反应靶基因。我们还发现，BMAL2是必要的稳定HIF 1A暴露于缺氧，但不稳定HIF 2A缺氧。这些数据表明，BMAL2是一个主转录调节缺氧反应PDAC，并可能作为一个长期寻找的分子开关，区分HIF 1A和HIF 2A依赖模式的缺氧代谢。
To identify drivers of malignancy in human pancreatic ductal adenocarcinoma (PDAC), we performed regulatory network analysis on a large collection of expression profiles from laser capture microdissected samples of PDAC and benign precursors. We discovered that BMAL2 plays a role in the initiation, progression, post resection survival, and KRAS activity in PDAC. Functional analysis of BMAL2 target genes led us to hypothesize that it plays a role in regulating the response to hypoxia, a critical but poorly understood feature of PDAC physiology. Knockout of BMAL2 in multiple human PDAC cell lines revealed effects on viability and invasion, particularly under hypoxic conditions. Loss of BMAL2 also affected glycolysis and other metabolic processes. We found that BMAL2 directly regulates hypoxia-responsive target genes. We also found that BMAL2 is necessary for the stabilization of HIF1A upon exposure to hypoxia, but destabilizes HIF2A under hypoxia. These data demonstrate that BMAL2 is a master transcriptional regulator of hypoxia responses in PDAC and may serve as a long-sought molecular switch that distinguishes HIF1A- and HIF2A-dependent modes of hypoxic metabolism.