Lee Han-Teo, Lee Il-Hwan, Kim Jae-Hwan, Lee Sangho, Kwak Sojung, Suh Min-Young, Hwang In-Young, Kang Bu-Gyeong, Cha Sun-Shin, Lee Byung-Il, Lee Sang-Eun, Choi Jinmi, Roe Jae-Seok, Cho Eun-Jung, Youn Hong-Duk
National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Korea.
Cancers (Basel). 2021 Jul 8;13(14):3418. doi: 10.3390/cancers13143418.
2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) expression is upregulated in a variety of cancers and has been related to poor prognosis. However, despite this significance to cancer progression, the precise oncogenic mechanism of OGFOD1 is not understood. We demonstrated that OGFOD1 plays a role in enhancing the transcriptional activity of RNA polymerase II in breast cancer cells. OGFOD1 directly binds to the C-terminal domain of RNA polymerase II to alter phosphorylation status. The elimination of OGFOD1 resulted in decreased tumor development. Additionally, cell cycle-dependent kinase 7 and cell cycle-dependent kinase 9, critical enzymes for activating RNA polymerase II, phosphorylated serine 256 of OGFOD1, whereas a non-phosphorylated mutant OGFOD1 failed to enhance transcriptional activation and tumor growth. Consequently, OGFOD1 helps promote tumor growth by enhancing RNA polymerase II, whereas simultaneous phosphorylation of OGFOD1 by CDK enzymes is essential in stimulating RNA polymerase II-mediated transcription both in vitro and in vivo, and expression of target genes.
含2-酮戊二酸和铁依赖性加氧酶结构域蛋白1（OGFOD1）在多种癌症中表达上调，并且与预后不良有关。然而，尽管OGFOD1对癌症进展具有重要意义，但其确切的致癌机制尚不清楚。我们证明，OGFOD1在增强乳腺癌细胞中RNA聚合酶II的转录活性方面发挥作用。OGFOD1直接与RNA聚合酶II的C末端结构域结合以改变磷酸化状态。OGFOD1的消除导致肿瘤发展减少。此外，细胞周期依赖性激酶7和细胞周期依赖性激酶9是激活RNA聚合酶II的关键酶，它们使OGFOD1的丝氨酸256磷酸化，而非磷酸化的突变体OGFOD1未能增强转录激活和肿瘤生长。因此，OGFOD1通过增强RNA聚合酶II来促进肿瘤生长，而CDK酶对OGFOD1的同时磷酸化对于在体外和体内刺激RNA聚合酶II介导的转录以及靶基因的表达至关重要。
