Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes
Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes
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DOI：
10.1128/mcb.00079-17
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发表时间：
2017-06-01
影响因子：
5.3
通讯作者：
Ooia, Aikseng
中科院分区：
文献类型：
--
作者：
Kerins, Michael John;Vashisht, Ajay Amar;Ooia, Aikseng
编码三羧酸（TCA）循环酶富马酸水合酶（FH）的基因的种系突变引起称为遗传性平滑肌瘤病和肾细胞癌（HLRCC）的遗传性癌症综合征。HLRCC相关肿瘤具有双等位基因FH失活，导致TCA循环代谢产物富马酸盐蓄积。尽管已知富马酸盐蓄积可改变细胞信号传导，但富马酸盐是否以及如何赋予生长优势仍不清楚。在这里，我们表明，富马酸盐的积累赋予一个慢性增殖信号，通过破坏细胞铁信号。具体而言，富马酸盐共价修饰铁调节蛋白2（IRP2）上的半胱氨酸残基，使其无法抑制铁蛋白mRNA翻译。同时，富马酸盐通过激活NRF 2（核因子[红细胞衍生2]样2）转录因子增加铁蛋白基因转录。反过来，增加的铁蛋白水平促进促有丝分裂转录因子FOXM1（叉头盒蛋白M1）的表达。与此同时，临床HLRCC组织中FOXM1及其增殖相关靶基因的表达水平均升高。这一发现证明了FH失活如何赋予细胞生长优势。
Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC-associated tumors harbor biallelic FH inactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor [erythroid-derived 2]-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates how FH inactivation can endow cells with a growth advantage.