The HIF-1α antisense long non-coding RNA drives a positive feedback loop of HIF-1α mediated transactivation and glycolysis.
The HIF-1α antisense long non-coding RNA drives a positive feedback loop of HIF-1α mediated transactivation and glycolysis.
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HIF-1α 反义长非编码 RNA 驱动 HIF-1α 介导的反式激活和糖酵解的正反馈循环
DOI：
10.1038/s41467-021-21535-3
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发表时间：
2021-02-26
影响因子：
16.6
通讯作者：
Song E
中科院分区：
文献类型：
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作者：
Zheng F;Chen J;Zhang X;Wang Z;Chen J;Lin X;Huang H;Fu W;Liang J;Wu W;Li B;Yao H;Hu H;Song E
缺氧诱导因子-1（HIF-1）是癌细胞中葡萄糖代谢的主要驱动因子。在这里，我们证明了HIF-1α反义lncRNA，HIFAL，是维持和增强HIF-1α介导的反式激活和糖酵解所必需的。HIFAL通过将脯氨酰羟化酶3（PHD 3）募集到丙酮酸激酶2（PKM 2）中，诱导其脯氨酰羟化，并通过与异质核核糖核蛋白F（hnRNPF）结合，将PKM 2/PHD 3复合物引入细胞核，增强HIF-1α的反式激活。HIF-1α诱导HIFAL转录，形成正反馈环以维持HIF-1α的反式激活活性。临床上，HIFAL高表达与侵袭性乳腺癌表型和患者预后不良相关。此外，HIFAL过表达促进体内肿瘤生长，而靶向HIFAL和HIF-1α显著降低了它们对癌症生长的影响。总之，我们的研究结果表明HIFAL在HIF-1α驱动的反式激活和糖酵解中具有关键的调节作用，将HIFAL确定为癌症治疗的治疗靶点。据报道，HIF 1 α通过激活糖酵解来驱动肿瘤发生。在这里，作者表明，HIFAL，HIF 1 α反义长非编码RNA，和HIF 1 α形成一个积极的前馈环，这是HIF 1 α介导的代谢重编程和致癌作用所必需的。
Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits prolyl hydroxylase 3 (PHD3) to pyruvate kinase 2 (PKM2) to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with heterogeneous nuclear ribonucleoprotein F (hnRNPF) to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly reduces their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment. HIF1alpha is reported to drive tumourigenesis through activating glycolysis. Here, the authors show that HIFAL, the HIF1alpha antisense long non-coding RNA, and HIF1alpha form a positive feed-forward loop which is essential for HIF1a-mediated metabolic reprogramming and oncogenic role.
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影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
5.4
作者：
Chen, Dongru;Wu, Liping;Deng, Jianqing
通讯作者：
Deng, Jianqing
DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
DOI：
10.1073/pnas.0909353106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Lee, KangAe;Zhang, Huafeng;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
16.8
作者：
通讯作者：
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