Abstract
Simple SummaryAmong the causes of accelerating cancer properties, dysregulated transcription is considerably prominent in many cancers. However, it is difficult to target transcriptional machineries due to their fundamental importance. Compared to breast cancer cell lines, we found that OGFOD1 aggravates cancers by enhancing RNA polymerase II transcriptional activity and it is improved by cell cycle-dependent kinases. Overall, we uncovered the novel mechanism for how OGFOD1 maliciously functions in breast cancers, suggesting it as a rational cancer treatment target protein.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.
Highlights
In order to examine the role of OGFOD1 in breast cancer cell lines, we verified the expression level of OGFOD1 in MDA-MB-231, HCC1954, T47D, MCF7, and non-tumorexpression level of OGFOD1 in MDA-MB-231, HCC1954, T47D, MCF7, and non-tumorigenic igenic epithelial cell line MCF10A
Both protein and mRNA levels of OGFOD1 were epithelial cell line MCF10A. Both protein and mRNA levels of OGFOD1 were highly expressed highly expressed in breast cancer cells compared to epithelial cells (Figure 1A–C)
To continue to transcribe and fully enter the elongation cycle, P-TEFb subsequently phosphorylates D-ribofuranosylbenzimidazole sensitivity-inducing factor (DSIF) and NELF, which are released from RNA polymerase II [28,29]; cyclin-dependent kinase 7 (CDK7) is known to be required for activating CDK9 phosphorylation and CDK9-dependent downstream events [30]
Summary
Compared to breast cancer cell lines, we found that OGFOD1 aggravates cancers by enhancing RNA polymerase II transcriptional activity and it is improved by cell cycle-dependent kinases. We uncovered the novel mechanism for how OGFOD1 maliciously functions in breast cancers, suggesting it as a rational cancer treatment target protein. Expression is upregulated in a variety of cancers and has been related to poor prognosis. 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.
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