RSK Inhibition Rewires Kinase Networks in Esophageal Cancer (proteomics)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Xi Chen
PROVIDER: PXD064585 | iProX | Tue Jun 03 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Our study reveals that RSK inhibition reprograms kinase networks to enforce stress adaptation, maintaining oncogenic homeostasis despite perturbations. These findings highlight a potential therapeutic window for early intervention strategies, suggesting that combination strategies may enhance the efficacy of RSK-directed therapies in ESCC.
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Project description:Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is generally unresponsive to therapy. African Americans have an increased risk for esophageal squamous cell cancer (ESCC), the subtype that shows marked variation in geographic frequency. To identify key genes involved in ESC carcinogenesis in African Americans we conducted microarray expression profiling and found a significant dysregulation of genes encoding stress response and drug-metabolizing enzymes, mainly in NRF2 pathway. The involvement of NRF2 mediated oxidative damage represent a key step in the evolution of African American ESCC. Loss of activity of these enzymes would confer increased sensitivity of esophageal cells to xenobiotics, such as alcohol and tobacco smoke, and may account for the high incidence of ESCC in this ethnic group. The differential expression profile also indicates an inflammatory component and tissue regeneration in ESCC tumorigenesis. Together, these findings suggest a remarkable interplay of genetic and environmental factors in the pathogenesis of African American ESCC.
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Project description:Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death worldwide. Emerging evidence suggests that the androgen receptor (AR) is involved in ESCC tumorigenesis. However, how AR exerts its genomic functions in ESCC remains unknown. Here, by defining AR cistromes and analyzing androgen-regulated transcriptomes, we find that AR downregulates the majority of its target genes in ESCC cells. We further find that the pioneer factor GATA3 governs AR-repressed transcription by recruiting SMRT/HDAC3 co-repressors to target gene loci. Importantly, genetic inhibition of GATA3 or pharmacological inhibition of AR/HDAC3 relieves AR-mediated gene repression, leading to ESCC cell growth inhibition in vitro and in vivo. Our findings reveal molecular mechanisms underlying the oncogenomic function of AR in ESCC and identify the GATA3-directed AR transcriptional repression program as a therapeutic target for ESCC.
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Project description:Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC). Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.
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Project description:Immune checkpoint modulation is an emerging therapeutic strategy for the treatment of esophageal squamous cell cancer (ESCC), but current strategies only benefit a fraction of patients. Glucocorticoid-induced TNFR-related protein (GITR) is a costimulatory immune checkpoint molecule that, upon engagement, can induce anti-tumor activity in solid tumor models. Here, we performed RNA sequencing analysis following targeting of GITR with an agonist antibody (clone DTA-1) or isotype control in the 4-nitroquinoline-1-oxide (4-NQO) mouse model of ESCC.
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Project description:Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy and the major histological subtype of esophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of ESCC, few targetable genomic lesions were identified and no molecular-based therapy is available. To identify druggable candidates in this tumor, we performed high-throughput small-molecule inhibitor screening. The unbiased results led us to discover a highly potent anti-ESCC compound, THZ1, a newly developed covalent CDK7 inhibitor. Further in vitro and in vivo experiments showed that THZ1 has powerful anti-neoplastic properties against ESCC cells with minimal toxic effect on healthy tissues. Importantly, whole-transcriptome sequencing (RNA-Seq) revealed that low-dose THZ1 treatment led to selective inhibition of a number of oncogenic transcripts. Notably, further characterization of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with Super-Enhancer (SE). Moreover, SE analysis alone uncovered many lineage-specific master regulators in ESCC. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel oncogenes in the context of ESCC, such as PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase. Together, our integrative molecular approaches identified a catalog of SE-associated lineage-specific master regulators and oncogenic transcripts in ESCC, which will significantly promote the understanding of ESCC biology. The preclinical results of THZ1 may help establish the therapeutic merit of targeting transcriptional regulation program for the treatment of this deadly malignancy.
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Project description:Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy and the major histological subtype of esophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of ESCC, few targetable genomic lesions were identified and no molecular-based therapy is available. To identify druggable candidates in this tumor, we performed high-throughput small-molecule inhibitor screening. The unbiased results led us to discover a highly potent anti-ESCC compound, THZ1, a newly developed covalent CDK7 inhibitor. Further in vitro and in vivo experiments showed that THZ1 has powerful anti-neoplastic properties against ESCC cells with minimal toxic effect on healthy tissues. Importantly, whole-transcriptome sequencing (RNA-Seq) revealed that low-dose THZ1 treatment led to selective inhibition of a number of oncogenic transcripts. Notably, further characterization of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with Super-Enhancer (SE). Moreover, SE analysis alone uncovered many lineage-specific master regulators in ESCC. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel oncogenes in the context of ESCC, such as PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase. Together, our integrative molecular approaches identified a catalog of SE-associated lineage-specific master regulators and oncogenic transcripts in ESCC, which will significantly promote the understanding of ESCC biology. The preclinical results of THZ1 may help establish the therapeutic merit of targeting transcriptional regulation program for the treatment of this deadly malignancy.
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Project description:The cancer cells selectively promote the translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. The tRNA N7-methylguanosine (m7G) modification is not essential for yeast growth, but in mammals mis-regulations of tRNA m7G modification cause stem cell defect and developmental disorders. Here we found that tRNA m7G methyltransferase complex components METTL1 and WDR4 are elevated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. Functionally, depletion of METTL1 or WDR4 suppresses proliferation, migration, and invasion of ESCC cells. In addition, forced expression of METTL1 or WDR4 promotes ESCC progression depending on the tRNA m7G methyltransferase activity. Mechanistically, METTL1 knockdown leads to reduced tRNA m7G modification and decreased expression of m7G-modified tRNAs. Depletion of METTL1 selectively reduces the translation of a subset of oncogenic transcripts, including the genes related to mTOR signaling and autophagy in m7G related codon dependent manner. Rescue assays revealed the essential function of RPTOR/ULK1/autophagy axis in METTL1 driven ESCC progression. Furthermore, ESCC initiation and progression models using Mettl1 conditional knockout and knockin mice uncovered the strong physiological function of Mettl1 in promoting in vivo ESCC tumorigenesis. Our study uncovered a new layer of translation regulation mechanism mediated by tRNA m7G modification, provided strong evidence to support the important physiological function of mis-regulated tRNA modification in cancer, and suggested that targeting METTL1 and its downstream signaling axis could be a promising strategy for ESCC treatment.
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Project description:Esophageal cancer is a lethal malignancy with high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are stillis poorly understood. Here we found that the N6-methyladenosine (m6A) methyltransferase METTL3 is significantly up-regulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that Mettl3 mediated m6A modification is essential for promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of Mettl3 in promoting in vivo ESCC tumorigenesis in vitro and in vivo. Mechanistically, Mettl3 catalyzed m6A modification promotes NOTCH1 expression and the activation of Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration and invasion capacities of METTL3 depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment.
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Project description:Esophageal squamous cell carcinoma (ESCC) is a serious cancer with a poor prognosis and a high recurrence rate after chemotherapy, which is a major clinical challenge. To elucidate the molecular basis of chemotherapy (chemo)-resistance and develop methods to effectively eliminate chemo-resistant tumor clones, we established a cancer organoid model from 24 ESCC patients of various stages, ages, and treatments. These ESCCOs recapitulated most oncogenic mutations of primary ESCC tissues and had tumorigenic properties upon xenografting. Each organoid line differs in its responsiveness to 5-fluorouracil (5-FU) and cisplatin (CDDP), chemotherapeutic agents commonly used to treat ESCC patients, with 7 lines exhibiting potent chemo-resistance. Importantly, these chemo-resistant ESCCOs had enhanced expression of genes involved in antioxidant stress response pathways and increased chromatin accessibility of their genomic loci, compared to chemo-sensitive ESCCOs, and these genes became useful biomarkers that can stratify chemo-resistant ESCC in histopathological specimens.
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