P4HA1/HIF1α feedback loop drives the glycolytic and malignant phenotypes of pancreatic cancer
P4HA1/HIF1α feedback loop drives the glycolytic and malignant phenotypes of pancreatic cancer
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DOI：
10.1016/j.bbrc.2019.06.096
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发表时间：
2019-08-27
影响因子：
3.1
通讯作者：
Zhu, Z. M.
中科院分区：
文献类型：
--
作者：
Cao, X. P.;Cao, Y.;Zhu, Z. M.
缺氧诱导因子1 α（HIF 1 α）的激活与多种恶性肿瘤的发生和发展密切相关。脯氨酰4-羟化酶亚基α 1（P4 HA 1）是脯氨酰4-羟化酶的活性催化组分，据报道可促进多种癌症的肿瘤进展。在这项研究中，我们发现P4 HA 1在胰腺导管腺癌（PDAC）中高表达，并预测了不良的临床结局。值得注意的是，PDAC细胞中P4 HA 1的表达升高是HIF 1 α依赖性的。癌症基因组图谱（TCGA）队列的基因集富集分析表明，PDAC中P4 HA 1表达与糖酵解和缺氧基因特征之间存在密切联系。P4 HA 1的敲除显著抑制PDAC细胞的糖酵解活性，如通过降低葡萄糖利用和乳酸产生所揭示的。因此，P4 HA 1与糖酵解基因之间存在着密切的相关性。此外，我们发现P4 HA 1可以增强HIFIa稳定性，表明PDAC中HIFIa和P4 HA 1之间存在正反馈回路。P4 HA 1基因沉默显著抑制PDAC细胞的增殖、耐药性和干细胞性。总的来说，我们的研究结果确定了P4 HA 1-HIF 1 α环作为糖酵解和PDAC致癌活性的关键调节因子，并为胰腺癌治疗提供了潜在的靶点。(C)2019爱思唯尔公司All rights reserved.
Hypoxia-inducible factor 1 alpha (HIF1 alpha) activation is profoundly implicated in the initiation and progression of multiple malignant tumors. Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is the active catalytic component of prolyl 4-hydroxylase and has been reported to promote tumor progression in several cancers. In this study, we revealed that P4HA1 was highly expressed in pancreatic ductal adenocarcinoma (PDAC) and predicted a poor clinical outcome. Notably, elevated expression of P4HA1 in PDAC cells was HIF1 alpha-dependent. Gene set enrichment analysis of The Cancer Genome Atlas (TCGA) cohort demonstrated a close link between P4HA1 expression and glycolysis and hypoxia gene signatures in PDAC. Knockdown of P4HA1 significantly suppressed the glycolytic activity of PDAC cells as revealed by reduced glucose utilization and lactate production. Consistently, there was a close correlation between P4HA1 and glycolysis genes. Moreover, we found that P4HA1 can enhance HIFI a stability, indicating a positive feedback loop between HIFI a and P4HA1 in PDAC. Genetic silencing of P4HA1 significantly inhibited the cell proliferation, chemoresistance, and sternness of PDAC cells. Collectively, our findings identify the P4HA1-HIF1 alpha loop as a critical regulator in glycolysis and oncogenic activities of PDAC and provide a potential target for pancreatic cancer treatment. (C) 2019 Elsevier Inc. All rights reserved.