Phosphorylation of Ser6 in hnRNPA1 by S6K2 regulates glucose metabolism and cell growth in colorectal cancer.
Phosphorylation of Ser6 in hnRNPA1 by S6K2 regulates glucose metabolism and cell growth in colorectal cancer.
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S6K2 对 hnRNPA1 中 Ser6 的磷酸化可调节结直肠癌中的葡萄糖代谢和细胞生长。
DOI：
10.3892/ol.2017.7085
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发表时间：
2017-12
期刊：
影响因子：
2.9
通讯作者：
Hu Y
中科院分区：
文献类型：
--
作者：
Sun Y;Luo M;Chang G;Ren W;Wu K;Li X;Shen J;Zhao X;Hu Y
葡萄糖代谢异常对于结直肠癌 (CRC) 的发展至关重要。丙酮酸激酶 (PK) M2 同工型（而不是 PKM1 同工型）的表达在重新编程癌细胞的葡萄糖代谢中发挥重要作用。 PKM2的优先表达主要是由选择性剪接驱动的，选择性剪接是由一组剪接因子协调的，包括异质核核糖核蛋白(hnRNP)A1、hnRNPA2和含有RNA结合基序的剪接因子。然而，与癌细胞表达 PKM2（而不是 PKM1）相关的潜在分子机制仍不清楚。分析 CRC 细胞中 PKM 亚型和葡萄糖代谢的 mRNA 水平。本研究结果表明，S6激酶2（S6K2）通过调节PKM基因的选择性剪接促进CRC细胞的糖酵解和生长。此外，染色质免疫沉淀分析表明，hnRNPA1 Ser6 的 S6K2 磷酸化促进了 hnRNPA1 与 PKM 基因剪接位点的结合。结果，癌细胞优先表达 PKM2 同工型，而不是 PKM1 同工型。此外，Cox 回归分析表明，hnRNPA1 Ser6 的磷酸化是 CRC 患者预后不良的预测因子。因此，本研究的结果揭示了S6K2对hnRNPA1中Ser6的磷酸化是葡萄糖代谢重编程的一种新机制，并表明S6K2是CRC治疗的潜在治疗靶点。
Abnormal glucose metabolism is critical in colorectal cancer (CRC) development. Expression of the pyruvate kinase (PK) M2 isoform, rather than the PKM1 isoform, serves important functions in reprogramming the glucose metabolism of cancer cells. Preferential expression of PKM2 is primarily driven by alternative splicing, which is coordinated by a group of splicing factors including heterogeneous nuclear ribonucleoprotein (hnRNP)A1, hnRNPA2 and RNA binding motif containing. However, the underlying molecular mechanisms associated with cancer cell expression of PKM2, instead of PKM1, remain unknown. The mRNA levels of PKM isoform and glucose metabolism were analyzed in CRC cells. The results of the present study indicated that S6 kinase 2 (S6K2) promotes glycolysis and growth of CRC cells by regulating alternative splicing of the PKM gene. In addition, chromatin immunoprecipitation assay indicated that S6K2 phosphorylation of Ser6 of hnRNPA1 facilitated hnRNPA1 binding to the splicing site of the PKM gene. As a result, cancer cells preferentially expressed the PKM2 isoform, instead of the PKM1 isoform. Furthermore, Cox regression analysis demonstrated that the phosphorylation of Ser6 of hnRNPA1 was a predictor of poor prognosis for patients with CRC. Therefore, the results of the present study revealed that the phosphorylation of Ser6 in hnRNPA1 by S6K2 was a novel mechanism underlying glucose metabolic reprogramming, and suggested that S6K2 is a potential therapeutic target for CRC treatment.
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S6K2：被忽视的 S6 激酶家族成员。
影响因子：
4.7
作者：
Pardo OE;Seckl MJ
通讯作者：
Seckl MJ
miR-124、miR-137 和 miR-340 通过抑制 Warburg 效应来调节结直肠癌的生长。
影响因子：
4.2
作者：
Sun, Yan;Zhao, Xiaoping;Hu, Yu
通讯作者：
Hu, Yu
丙酮酸激酶M2激活剂促进四聚体形成并抑制肿瘤发生。
影响因子：
14.8
作者：
Anastasiou, Dimitrios;Yu, Yimin;Israelsen, William J.;Jiang, Jian-Kang;Boxer, Matthew B.;Hong, Bum Soo;Tempel, Wolfram;Dimov, Svetoslav;Shen, Min;Jha, Abhishek;Yang, Hua;Mattaini, Katherine R.;Metallo, Christian M.;Fiske, Brian P.;Courtney, Kevin D.;Malstrom, Scott;Khan, Tahsin M.;Kung, Charles;Skoumbourdis, Amanda P.;Veith, Henrike;Southall, Noel;Walsh, Martin J.;Brimacombe, Kyle R.;Leister, William;Lunt, Sophia Y.;Johnson, Zachary R.;Yen, Katharine E.;Kunii, Kaiko;Davidson, Shawn M.;Christofk, Heather R.;Austin, Christopher P.;Inglese, James;Harris, Marian H.;Asara, John M.;Stephanopoulos, Gregory;Salituro, Francesco G.;Jin, Shengfang;Dang, Lenny;Auld, Douglas S.;Park, Hee-Won;Cantley, Lewis C.;Thomas, Craig J.;Heiden, Matthew G. Vander
通讯作者：
Heiden, Matthew G. Vander
影响因子：
5.6
作者：
Jean-Philippe J;Paz S;Caputi M
通讯作者：
Caputi M
影响因子：
8
作者：
Calabretta S;Bielli P;Passacantilli I;Pilozzi E;Fendrich V;Capurso G;Fave GD;Sette C
通讯作者：
Sette C