Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer.
Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer.
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细胞内 CYTL1 是一种新型肿瘤抑制因子，可稳定 NDUFV1 以抑制乳腺癌中的代谢重编程
DOI：
10.1038/s41392-021-00856-1
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发表时间：
2022-02-04
影响因子：
39.3
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Xue W;Li X;Li W;Wang Y;Jiang C;Zhou L;Gao J;Yu Y;Shen Y;Xu Q
功能丧失突变经常发生在肿瘤抑制基因中，即，p53，在各种癌症的恶性进展过程中。任何内在抑制基因是否携带罕见的突变在很大程度上是未知的。在这里，我们证明了细胞内的类谷氨酰胺蛋白1（CYTL 1）在防止乳腺癌的糖酵解转换特征中起着关键作用。代谢重编程需要低细胞内CYTL 1水平，而不是其突变。表达缺乏1-22 aa信号肽的细胞内形式CYTL 1（Δ CYTL 1）的乳腺癌细胞显示出显著减弱的葡萄糖摄取和乳酸产生，这与体外和体内细胞生长和转移的抑制有关。从机制上讲，CYTL 1竞争性结合NDUFV 1的N-末端序列，以阻断MDM 2介导的蛋白酶体降解，导致NDUFV 1蛋白的稳定性。除了诱导增加的NAD+水平外，NDUFV 1与Src相互作用以减弱酪氨酸10处的LDHA磷酸化并减少乳酸产生。我们的研究结果首次揭示了CYTL 1是一种新的肿瘤抑制因子。它在逆转代谢重编程向糖酵解的功能可能是非常重要的新的抗肿瘤策略的发展。
Loss-of-function mutations frequently occur in tumor suppressor genes, i.e., p53, during the malignant progression of various cancers. Whether any intrinsic suppressor carries a rare mutation is largely unknown. Here, we demonstrate that intracellular cytokine-like protein 1 (CYTL1) plays a key role in preventing the robust glycolytic switching characteristic of breast cancer. A low intracellular CYTL1 level, not its mutation, is required for metabolic reprogramming. Breast cancer cells expressing an intracellular form of CYTL1 lacking a 1-22 aa signal peptide, ΔCYTL1, show significantly attenuated glucose uptake and lactate production, which is linked to the inhibition of cell growth and metastasis in vitro and in vivo. Mechanistically, CYTL1 competitively binds the N-terminal sequence of NDUFV1 to block MDM2-mediated degradation by the proteasome, leading to the stability of the NDUFV1 protein. In addition to inducing increased NAD+ levels, NDUFV1 interacts with Src to attenuate LDHA phosphorylation at tyrosine 10 and reduce lactate production. Our results reveal, for the first time, that CYTL1 is a novel tumor suppressor. Its function in reversing metabolic reprogramming toward glycolysis may be very important for the development of novel antitumor strategies.
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