Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA448451 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6927780.fastq.gz | Fastqsanger.gz | |||
| SRR6927790.fastq.gz | Fastqsanger.gz | |||
| SRR6927800.fastq.gz | Fastqsanger.gz | |||
| SRR6927810.fastq.gz | Fastqsanger.gz | |||
| SRR6927820.fastq.gz | Fastqsanger.gz |
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Project description:The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.
2018-10-26 | GSE112608 | GEO
Project description:The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and is expressed in a strictly growth factor-dependent manner in non-tumor cells. Here we show that MYC directly binds SPT5, a subunit of the RNA polymerase II (POL2) elongation factor DSIF. MYC recruits SPT5 to genes and enables the CDK7-dependent transfer of SPT5 onto POL2. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. In addition, MYC increases the directionality of promoters by stimulating sense transcription and suppressing the synthesis of antisense RNAs. Our results argue that MYC controls the productive assembly of POL2 with general elongation factors to form processive elongation complexes. The high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, slows transcription at growth-suppressive genes and promotes uncontrolled cellular growth.
2019-03-27 | GSE115365 | GEO
Project description:The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.
| S-EPMC6422358 | biostudies-literature
Project description:The elongation stage of transcription is a highly regulated in metazoan. We previously purified the AFF1/AFF4-containing Super Elongation Complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL, and AF9. The SEC family members demonstrate high levels of Pol II CTD kinase activity, however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-seq analyses demonstrate that SEC-L2-3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid gene expression in cells. MYC is one of the direct targets of AFF4/SEC, and the SEC requirement to the MYC gene regulates its expression in different cancer cells bearing either acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression. RNA-seq in human embyonic kidney 293T cells of wild-type and after RNAi of AFF2, AFF3, AFF4. ChIP-seq of AFF4 and Pol2 in human 293T cells.
2012-05-01 | E-GEOD-34097 | biostudies-arrayexpress
Project description:The elongation stage of transcription is a highly regulated in metazoan. We previously purified the AFF1/AFF4-containing Super Elongation Complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL, and AF9. The SEC family members demonstrate high levels of Pol II CTD kinase activity, however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-seq analyses demonstrate that SEC-L2-3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid gene expression in cells. MYC is one of the direct targets of AFF4/SEC, and the SEC requirement to the MYC gene regulates its expression in different cancer cells bearing either acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression.
2012-05-02 | GSE34097 | GEO
Project description:MYCN amplification in neuroblastoma predicts particular poor prognosis and directly targeting of MYCN remains a major challenge. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastoma. Mechanistically, MYCN directly interacts with the SEC subunit EAF1 and recruits the complex to the target gene loci for ensuing processive transcription elongation, rendering MYCN-mediated transcriptional activation highly dependent on SEC. Pharmacological inhibition of SEC by KL-1 or KL-2 elicits selective cell death in MYCN-overexpressing neuroblastoma cells. Furthermore, drug combination screening identifies the BCL-2 inhibitor ABT-199 synergistic with KL-2. Pre-clinical studies manifest that KL-2 and ABT-199 co-treatment significantly suppresses tumorigenesis and shows therapeutic value in multiple neuroblastoma allograft and xenograft models. These findings highlight SEC as a targetable vulnerability, and simultaneous inhibition of SEC and BCL-2 holds great promise for the treatment of MYCN-driven neuroblastoma.
2023-02-27 | GSE199086 | GEO
Project description:MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation
| PRJNA474714 | ENA
Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
2023-05-10 | PXD039332 | Pride
Project description:The AF4/FMR2 proteins AFF1 and AFF4 act as a scaffold to assemble the Super Elongation Complex (SEC) that strongly activates transcriptional elongation of HIV-1 and cellular genes. Although they can dimerize, it is unclear whether the dimers exist and function within a SEC in vivo. Furthermore, it is unknown whether AFF1 and AFF4 function similarly in mediating SEC-dependent activation of diverse genes. Providing answers to these questions, our current study shows that AFF1 and AFF4 reside in separate SECs that display largely distinct gene target specificities. While the AFF1-SEC is more potent in supporting HIV-1 transactivation by the viral Tat protein, the AFF4-SEC is more important for HSP70 induction upon heat shock. The functional difference between AFF1 and AFF4 in Tat-transactivation has been traced to a single amino acid variation between the two proteins, which causes them to enhance the affinity of Tat for P-TEFb, a key SEC component, with different efficiency. Finally, genome-wide analysis confirms that the genes regulated by AFF1- and AFF4-SEC are largely non-overlapping and perform distinct functions. Thus, the SEC represents a family of related complexes that exist to increase the regulatory diversity and gene control options during transactivation of diverse cellular and viral genes. RNA-seq in HeLa cells of wild-type and after RNAi of AFF1 or AFF4.
2015-05-20 | E-GEOD-69021 | biostudies-arrayexpress
Project description:The AF4/FMR2 proteins AFF1 and AFF4 act as a scaffold to assemble the Super Elongation Complex (SEC) that strongly activates transcriptional elongation of HIV-1 and cellular genes. Although they can dimerize, it is unclear whether the dimers exist and function within a SEC in vivo. Furthermore, it is unknown whether AFF1 and AFF4 function similarly in mediating SEC-dependent activation of diverse genes. Providing answers to these questions, our current study shows that AFF1 and AFF4 reside in separate SECs that display largely distinct gene target specificities. While the AFF1-SEC is more potent in supporting HIV-1 transactivation by the viral Tat protein, the AFF4-SEC is more important for HSP70 induction upon heat shock. The functional difference between AFF1 and AFF4 in Tat-transactivation has been traced to a single amino acid variation between the two proteins, which causes them to enhance the affinity of Tat for P-TEFb, a key SEC component, with different efficiency. Finally, genome-wide analysis confirms that the genes regulated by AFF1- and AFF4-SEC are largely non-overlapping and perform distinct functions. Thus, the SEC represents a family of related complexes that exist to increase the regulatory diversity and gene control options during transactivation of diverse cellular and viral genes.
2015-05-20 | GSE69021 | GEO