Targeting an RNA polymerase II-associated PHF5A transcriptional subcomplex with a KMT2A-WDR5 inhibitor impairs self-renewal and tumorigenicity of pancreatic cancer stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA898395 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Pancreatic cancer (PC) remains one of the most aggressive and life-threatening malignancies known for its notorious resistance to chemotherapy. This is increasingly ascribed to the subpopulation of undifferentiated cells, known as pancreatic cancer stem cells (PCSCs), which are evolutionary fitter than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are crucial for tumor relapse as they possess ‘stem cell-like’ features of self-renewal and differentiation. However, what molecular mechanisms maintain the unique characteristics of PCSCs are poorly understood. Here, we identified an RNA polymerase II-associated PHF5A-PHF14-HMG20A-RAI1-KMT2A transcriptional subcomplex, which regulates the stemness characteristics and tumorigenicity of PCSCs through epigenetic control of gene expression. Targeting the protein subcomplex with a KMT2A-WDR5 inhibitor attenuated the self-renewal and in vivo tumorigenicity of PCSCs, thus offering a novel anti-PCSCs targeting strategy for enhancing the efficiency of chemotherapy which is likely to translate into durable clinical responses in PC patients.
2023-08-23 | PXD038378 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-08-10 | GSE217332 | GEO
Project description:Pancreatic cancer remains one of the most aggressive and lethal cancers in humans. It is undeniably known for its notorious resistance to conventional chemotherapeutics which are often associated with a transient response to treatment but rapidly followed by drug resistance and tumor recurrence. Increasing evidence suggests that therapy failure in pancreatic cancer is largely ascribed to the residual subpopulation of undifferentiated cells, known as cancer stem cells (CSCs), which are evolutionary 'fitter' than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are outstandingly critical for tumor relapse as they possess unique 'stem cell-like' features of self-renewal and differentiation which render them capable of regenerating the original tumor. Through the identification of key epigenetic regulators of CSCs phenotypes and functions, this project seeks to gain insight into the molecular mechanisms underlying tumor recurrence and identify novel therapeutic candidates for eliminating CSCs and achieving long-term clinical responses in pancreatic cancer patients.
2023-08-10 | GSE217331 | GEO
Project description:Pancreatic cancer remains one of the most aggressive and lethal cancers in humans. It is undeniably known for its notorious resistance to conventional chemotherapeutics which are often associated with a transient response to treatment but rapidly followed by drug resistance and tumor recurrence. Increasing evidence suggests that therapy failure in pancreatic cancer is largely ascribed to the residual subpopulation of undifferentiated cells, known as cancer stem cells (CSCs), which are evolutionary 'fitter' than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are outstandingly critical for tumor relapse as they possess unique 'stem cell-like' features of self-renewal and differentiation which render them capable of regenerating the original tumor. Through the identification of key epigenetic regulators of CSCs phenotypes and functions, this project seeks to gain insight into the molecular mechanisms underlying tumor recurrence and identify novel therapeutic candidates for eliminating CSCs and achieving long-term clinical responses in pancreatic cancer patients.
2023-08-10 | GSE217329 | GEO
Project description:Pancreatic cancer remains one of the most aggressive and lethal cancers in humans. It is undeniably known for its notorious resistance to conventional chemotherapeutics which are often associated with a transient response to treatment but rapidly followed by drug resistance and tumor recurrence. Increasing evidence suggests that therapy failure in pancreatic cancer is largely ascribed to the residual subpopulation of undifferentiated cells, known as cancer stem cells (CSCs), which are evolutionary 'fitter' than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are outstandingly critical for tumor relapse as they possess unique 'stem cell-like' features of self-renewal and differentiation which render them capable of regenerating the original tumor. Through the identification of key epigenetic regulators of CSCs phenotypes and functions, this project seeks to gain insight into the molecular mechanisms underlying tumor recurrence and identify novel therapeutic candidates for eliminating CSCs and achieving long-term clinical responses in pancreatic cancer patients.
2023-08-10 | GSE217330 | GEO
Project description:Pancreatic cancer (PC), one of the most aggressive and life-threatening human malignancies, is known for its resistance to cytotoxic therapies. This is increasingly ascribed to the subpopulation of undifferentiated cells, known as pancreatic cancer stem cells (PCSCs), which display greater evolutionary fitness than other tumor cells to evade the cytotoxic effects of chemotherapy. PCSCs are crucial for tumor relapse as they possess 'stem cell-like' features that are characterized by self-renewal and differentiation. However, the molecular mechanisms that maintain the unique characteristics of PCSCs are poorly understood. Here, we identify the histone methyltransferase KMT2A as a physical binding partner of an RNA polymerase-associated PHF5A-PHF14-HMG20A-RAI1 protein subcomplex and an epigenetic regulator of PCSC properties and functions. Targeting the protein subcomplex in PCSCs with a KMT2A-WDR5 inhibitor attenuates their self-renewal capacity, cell viability, and in vivo tumorigenicity.
| S-EPMC10502114 | biostudies-literature
Project description:The highly conserved WD40-repeat protein WDR5 is part of multiple functional complexes both inside and outside the nucleus, interacting with the MLL/SET1 histone methyltransferases that catalyze histone H3 lysine 4 (H3K4) di- and tri-methylation (me2,3), and KIF2A, a member of the Kinesin-13 family of microtubule depolymerase. It is currently unclear whether, and how, the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein dually encoded in the human SCRIB gene regulates the association of WDR5 with epigenetic and KIF2A complexes. We propose to name this alt-protein EMBOW, or microprotein that is the epigenetic to mitotic binder of WDR5. Loss of EMBOW decreases WDR5 interaction with KIF2A, displaces WDR5 from the spindle pole during G2/M phase, and shortens the spindle length, hence prolonging G2/M phase and delaying cell proliferation. On the other hand, loss of EMBOW increases WDR5 interaction with epigenetic complexes, including KMT2A/MLL1, and promotes WDR5 association with chromatin and binding to the target genes, hence increasing H3K4me3 levels of target genes. Together, these results implicate EMBOW as a regulator of WDR5 that switches it between epigenetic and mitotic regulatory roles during cell cycle, explaining how mammalian cells can temporally control the multifunctionality of WDR5.
2023-09-19 | PXD036699 | Pride
Project description:Developing small-molecule splicing modulators represents a promising therapeutic approach for various diseases. Natural products such as pladienolide, herboxidiene, and spliceostatin have been identified as potent splicing modulators that target SF3B1 in the SF3b subcomplex. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, and SF3B1-V1078 confer resistance to these modulators, suggesting a common site of interaction. Whole-transcriptome RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but alters the action of splicing modulators from inducing intron-retention to exon-skipping. Relative intron strength to splicing inhibition correlates with the differential in GC content between adjacent introns and exons, leading to this differential global splicing pattern. We determine the crystal structure of human PHF5A and find that Y36 is located on the surface in a region of high sequence conservation. Structural analysis of the cryo-EM spliceosome Bact complex shows that these mutations cluster in a well-defined pocket surrounding the branch point adenosine suggesting a possible competitive mode of action for these splicing modulators, which interact with the aromatic side-chain of PHF5A-Y36. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these small-molecule splicing modulators, offering insights to modulate splicing.
2017-05-25 | GSE96917 | GEO
Project description:Background: Cholangiocarcinoma (CCA) is a high malignancy, rapid progression tumor of bile duct. Due to its chemoresistance, it always has an extremely poor prognosis. Therefore, it is still need to detailed elucidation the mechanisms of chemoresistance and find the therapeutic targets. Methods: We analysis the expression of MBD2 in CCA and normal bile duct tissues through public database and immunohistochemical (IHC). The role of MBD2 in CCA cells’ proliferation, migration, chemoresistance ability was validated through CCK-8, plate clone assay, wound healing assay, xenograft mice models. Besides, we construct a primary CCA mice model to further confirm the effect of MBD2. RNA-seq, co-IP-MS were used to find the mechanisms of MBD2 leading to chemoresistance. Results: MBD2 is up-regulated in CCA. It could promote the proliferation, migration and chemoresistance of CCA cells. Mechanistically, MBD2 could directly interact with WDR5, and binding to the promoter of ABCB1, then promote the tri-methylation of H3K4 in this region through KMT2A, active the expression of ABCB1. Knocking down of WDR5 or KMT2A could block the transcriptional activation of ABCB1 by MBD2. MM-102 is a molecular inhibitor that targets the interaction of WDR5 with KMT2A. MM-102 could inhibit the expression of ABCB1 in CCA cells, and decrease the chemoresistance of CCA to cisplatin. Conclusion: MBD2 promote the progress and chemoresistance of CCA through interact with WDR5. MM-102 could effectively block this procedure and enhance the sensitivity to cisplatin of CCA.
2024-09-30 | GSE275477 | GEO