Suppressing Aberrant Hedgehog Pathway and Overcoming Resistance to Smoothened Antagonists via Targeting Super-enhancer-driven Transcriptional Dependencies
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE266391 | GEO | 2024/05/16
REPOSITORIES: GEO
Similar Datasets
Project description:Aberrant activation of Hedgehog (Hh) signaling pathway plays important roles in both oncogenesis and targeted therapy of many cancers. The clinical application of FDA-approved Hh-targeted Smoothened inhibitor (SMOi) drugs is hindered due to the emergence of various primary or acquired drug resistance, indicating the need of novel anti-Hh therapies. Our previous studies demonstrate that epigenetic/transcriptional targeted therapies represent a promising direction for anti-Hh drug development. In this study, we identified CDK9 and CDK12, two transcription elongation regulators, as novel therapeutic targets for antagonizing the aberrant Hh pathway and overcoming SMOi resistance. CDK9 inhibition and CDK12 inhibition exhibited similarly potent anti-Hh activities when treating various SMOi responsive or resistant Hh-driven tumor models as previously reported BET inhibition or CDK7 inhibition. We also utilized SHH-subtype medulloblastoma (SHH-MB) as the representative Hh-driven cancer model to perform Super-enhancer (SE) analysis and elucidate the crucial roles of SE in Hh-driven oncogenesis and above-mentioned anti-Hh epigenetic/transcriptional targeted therapies. Furthermore, we identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target of multiple Hh-driven tumor models, including the SMOi-resistant ones. Collectively, our study demonstrates that the SE-driven transcriptional dependencies represent promising therapeutic vulnerabilities for suppressing the aberrant Hh pathway and overcoming the SMOi resistance. As CDK9 inhibitor and IRS inhibitor drugs have already entered human clinical trials for cancer treatment, our study provides comprehensive preclinical support for expanding their trials to Hh-driven cancers in near future.
2024-05-16 | GSE266389 | GEO
Project description:Aberrant activation of Hedgehog (Hh) signaling pathway plays important roles in both oncogenesis and targeted therapy of many cancers. The clinical application of FDA-approved Hh-targeted Smoothened inhibitor (SMOi) drugs is hindered due to the emergence of various primary or acquired drug resistance, indicating the need of novel anti-Hh therapies. Our previous studies demonstrate that epigenetic/transcriptional targeted therapies represent a promising direction for anti-Hh drug development. In this study, we identified CDK9 and CDK12, two transcription elongation regulators, as novel therapeutic targets for antagonizing the aberrant Hh pathway and overcoming SMOi resistance. CDK9 inhibition and CDK12 inhibition exhibited similarly potent anti-Hh activities when treating various SMOi responsive or resistant Hh-driven tumor models as previously reported BET inhibition or CDK7 inhibition. We also utilized SHH-subtype medulloblastoma (SHH-MB) as the representative Hh-driven cancer model to perform Super-enhancer (SE) analysis and elucidate the crucial roles of SE in Hh-driven oncogenesis and above-mentioned anti-Hh epigenetic/transcriptional targeted therapies. Furthermore, we identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target of multiple Hh-driven tumor models, including the SMOi-resistant ones. Collectively, our study demonstrates that the SE-driven transcriptional dependencies represent promising therapeutic vulnerabilities for suppressing the aberrant Hh pathway and overcoming the SMOi resistance. As CDK9 inhibitor and IRS inhibitor drugs have already entered human clinical trials for cancer treatment, our study provides comprehensive preclinical support for expanding their trials to Hh-driven cancers in near future.
2024-05-16 | GSE266386 | GEO
Project description:Suppressing Aberrant Hedgehog Pathway and Overcoming Resistance to Smoothened Antagonists via Targeting Super-enhancer-driven Transcriptional Dependencies
| PRJNA1106892 | ENA
Project description:Suppressing Aberrant Hedgehog Pathway and Overcoming Resistance to Smoothened Antagonists via Targeting Super-enhancer-driven Transcriptional Dependencies [RNA-seq]
| PRJNA1106896 | ENA
Project description:Suppressing Aberrant Hedgehog Pathway and Overcoming Resistance to Smoothened Antagonists via Targeting Super-enhancer-driven Transcriptional Dependencies [ChIP-seq]
| PRJNA1106888 | ENA
Project description:The aberrant hedgehog (Hh) pathway plays important roles in multiple cancer types, therefore serving as a promising drug target. Current clinically available hedgehog-targeted drugs act mostly by antagonizing the upstream component smoothened; however, both primary and acquired resistance to FDA-approved smoothened inhibitor (SMOi) drugs have been described. We have recently demonstrated that the BET inhibitor effectively suppresses SMOi-resistant Hh-driven cancers through antagonizing transcription of GLI1 and GLI2, the core transcriptional factors of Hh pathway, suggesting epigenetic or transcriptional targeted therapy represents an anti-Hh therapeutic strategy that can overcome SMOi resistance. Here we performed an unbiased screening of epigenetic or transcriptional targeted small molecules to test their inhibitory effects on GLI1 and GLI2 transcription or cell viability of Hh-driven tumor lines. THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), is identified as the top hit in our screening. We then confirmed that antagonizing CDK7 by either small-molecule inhibitors or the CRISPR-Cas9 approach causes substantial suppression of GLI1 and GLI2 transcription, resulting in effective inhibition of Hh-driven cancers in vitro and in vivo. More importantly, antagonizing CDK7 retains inhibitory activity against Hh-driven cancers with almost all so-far described primary or acquired SMOi resistance. Furthermore, we reveal a synergy between CDK7 inhibition and BET inhibition on antagonizing aberrant Hh pathway and Hh-driven cancers that are either responsive or resistant to SMOi. Our results illustrate transcriptional inhibition through targeting CDK7 as a promising therapeutic strategy for treating Hh-driven cancers, especially those with primary or acquired resistance to SMOi drugs.
| S-EPMC6600918 | biostudies-literature
Project description:Poor response of tumors to radiotherapy is a major clinical obstacle. Because of the dynamic characteristics of the epigenome, identification of possible epigenetic modifiers may be beneficial to confer radio-sensitivity. This research was set to examine the modulation of ectodermal-neural cortex 1 (ENC1) in radio-resistance in breast carcinoma (BC). In silico identification and immunohistochemical staining revealed that overexpression of ENC1 promoted BC metastasis to the bone and brain. Moreover, its overexpression promoted the translocation of YAP1/TAZ into the nucleus and enhanced expression of GLI1, CTGF, and FGF1 through the Hippo pathway. ENC1 expression was controlled by a ~10-kb long SE. ENC1-SEdistal deletion reduced ENC1 expression and inhibited the malignant behavior of BC cells and their resistance to radiotherapy. The binding sites on the ENC1-SE region enriched the shared sequence between TCF4 and ENC1 promoter. Knocking-down TCF4 inhibited luciferase activity and H3K27ac-enriched binding of the ENC1-SE region. Additionally, SE-driven ENC1 overexpression mediated by TCF4 may have clinical implications in radio-resistance in BC patients. Our findings indicated that ENC1 overexpression is mediated by SE and the downstream TCF4 to potentiate the Hippo/YAP1/TAZ pathway. Targeting this axis might be a therapeutic strategy for overcoming BC radio-resistance.
| S-EPMC8346480 | biostudies-literature
Project description:BackgroundMedulloblastoma is the most common malignant pediatric brain tumor and group 3 subtype medulloblastoma (G3-MB) exhibits the worst prognosis. Super enhancers (SEs) are large clusters of enhancers that play important roles in cancer through transcriptional control of cell identity genes, oncogenes and tumor-dependent genes. Dissecting SE-driven transcriptional dependencies of cancer leads to identification of novel oncogenic mechanisms, therapeutic strategies and targets.MethodsIntegrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB were performed to extract the conserved SE-associated gene signatures and their oncogenic potentials were evaluated by gene expression, tumor-dependency and patient prognosis analyses. SE-associated subtype-specific upregulated tumor-dependent genes, which were revealed as members of SE-driven core transcriptional regulatory network of G3-MB, were then subjected to functional validation and mechanistic investigation. SE-associated therapeutic potential was further explored by genetic or pharmaceutical targeting of SE complex components or SE-associated subtype-specific upregulated tumor-dependent genes individually or in combination, and the underlying therapeutic mechanisms were also examined.ResultsThe identified conserved SE-associated transcripts of G3-MB tissues and cell lines were enriched of subtype-specifically upregulated tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated G3-MB-specific upregulated tumor-dependent genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized TFs (MYC, OTX2 and CRX) and eleven newly identified downstream effector genes (ARL4D, AUTS2, BMF, IGF2BP3, KIF21B, KLHL29, LRP8, MARS1, PSMB5, SDK2 and SSBP3). An OTX2-SE-ARL4D regulatory axis was further revealed to represent a subtype-specific tumor dependency and therapeutic target of G3-MB via contributing to maintaining cell cycle progression and inhibiting neural differentiation of tumor cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector gene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB via stronger suppression of SE-associated transcription or higher induction of ER stress, respectively.ConclusionsOur study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic strategies and targets.
| S-EPMC9587669 | biostudies-literature
Project description:Hedgehog (Hh) signaling promotes tumorigenesis. The accumulation of the membrane protein Smoothened (Smo) within the primary cilium (PC) is a key event in Hh signal transduction, and many pharmacological inhibitors identified to date target Smo's actions. Smo ciliary translocation is inhibited by some pathway antagonists, while others promote ciliary accumulation, an outcome that can lead to a hypersensitive state on renewal of Hh signaling. To identify novel inhibitory compounds acting on the critical mechanistic transition of Smo accumulation, we established a high content screen to directly analyze Smo ciliary translocation. Screening thousands of compounds from annotated libraries of approved drugs and other agents, we identified several new classes of compounds that block Sonic hedgehog-driven Smo localization within the PC. Selective analysis was conducted on two classes of Smo antagonists. One of these, DY131, appears to inhibit Smo signaling through a common binding site shared by previously reported Smo agonists and antagonists. Antagonism by this class of compound is competed by high doses of Smo-binding agonists such as SAG and impaired by a mutation that generates a ligand-independent, oncogenic form of Smo (SmoM2). In contrast, a second antagonist of Smo accumulation within the PC, SMANT, was less sensitive to SAG-mediated competition and inhibited SmoM2 at concentrations similar to those that inhibit wild-type Smo. Our observations identify important differences among Hh antagonists and the potential for development of novel therapeutic approaches against mutant forms of Smo that are resistant to current therapeutic strategies.
| S-EPMC3905677 | biostudies-literature
Project description:Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of bromodomain and extra-terminal domain (BET) proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of bromodomain 4 (BRD4) at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.
| S-EPMC4018722 | biostudies-literature