June 22, 2024

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Cell: Discovered new checkpoints ( PP2A) that regulate gene transcription

Cell: Discovered new checkpoints ( PP2A) that regulate gene transcription and open up new ways of cancer treatment

 

Cell: Discovered new checkpoints ( PP2A) that regulate gene transcription.  Cancer is the result of gene mutations or changes in expression, because turning on or off one or more genes at the wrong time or in the wrong cell can significantly change its overall behavior, leading to unlimited cell growth.

Gene expression is strictly regulated, with RNA polymerase II (RNAPII) and cyclin-dependent kinase (CDK) acting in concert. The gene expression of RNA polymerase II (RNAPII) is strictly regulated by CDK9 during the transcription cycle. Although there are many studies on RNAPII-CDK, little is known about the phosphatase involved.

On May 17, 2021, researchers from the University of Melbourne in Australia and the Wistar Institute in the United States published a study titled: The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer in the Cell journal paper.

The research team discovered a new checkpoint that controls RNA polymerase II (RNAPII) gene transcription: protein phosphatase 2A (PP2A), and pointed out that this checkpoint can be used as a cancer treatment target, demonstrating that the new combination therapy can be used in animals. Anti-cancer effects in tumor models also provide new insights into how gene expression is strictly regulated.

Cell: Discovered new checkpoints ( PP2A) that regulate gene transcription

The research team first used CRISPR-Cas9 genome-wide CDK9-inhibited leukemia cell lines to screen for cell survival and found the selective enrichment of sgRNA for INTS6, indicating that INTS6 may play a role in regulating the CDK9 inhibition response.

Cell: Discovered new checkpoints ( PP2A) that regulate gene transcription

In order to determine how INTS6 regulates the transcriptional and biological response to CDK9i, the research team conducted liquid chromatography-tandem mass spectrometry (LC-MS/MS) and discovered the interaction between INTS6, RNAPII and PP2A, and recruited it to the transcription site. At this point, it counteracts CDK9 activity and blocks transcription elongation. PP2A and CDK9 work together to fine-tune the balance between transcriptional activation and repression.

Cell: Discovered new checkpoints ( PP2A) that regulate gene transcription

In order to evaluate the effect of INTS6/PP2A deletion on CDK9 inhibition-induced nascent transcription inhibition, the research team performed 4-thiouridine metabolic labeling in INTS6 knockout cells, and then performed RNA sequencing. They found that the loss of INTS6 resulted in resistance to CDK9 inhibition-mediated tumor cell death, a decrease in the turnover rate of CDK9 phosphate substrates, and an expansion of acute oncogenic transcriptional responses.

In preclinical models of leukemia and lymphoma, targeting CDK9 has a therapeutic effect. PP2A small molecule activators (SMAPs) can enhance the recruitment of PP2A to chromatin on actively transcribed genes. By simultaneously inhibiting CDK9 and SMAP-mediated PP2A activation, it provides a strong reason for targeting the PP2A-Integrator-CDK9 axis .

The research team evaluated the in vivo tumor treatment effects of CDK9 inhibitors and PP2A agonists in leukemia and solid tumor xenograft models, and found that inhibiting the PP2A-Integrator-CDK9 signal axis can treat mice with leukemia and solid tumors.

The combined application of CDK9 inhibitors and PP2A activators can kill acute myeloid leukemia cells. Compared with a single drug, it can prolong the efficacy and significantly extend the survival period. Similarly, the combination therapy in the solid tumor model showed a reduction in tumor growth rate and tumor volume, thereby improving overall survival.

In summary, the research team discovered a new checkpoint for fine-tuning RNA polymerase II (RNAPII) gene transcription, described a new basic mechanism of gene expression regulation, and demonstrated that CDK9 inhibition and PP2A activation can enhance solid tumors and The role of cancer therapy in preclinical models of hematological tumors has opened up a new approach for anticancer therapy based on gene transcription.

 

 

(source:internet, reference only)


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