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SETD2-mediated loss of a panel of miRNAs determines MAPK/JNK signaling pathway activation and multidrug resistance in renal cell carcinoma

ABSTRACT: Finding the downstream miRNAs of SETD2 in the renal cell carcinoma cell line the coordinated expression of SETD2-miRNAs-MAPK/JNK may be predictive of poor prognostic in patients with RCC. Our findings also emphasize the therapeutic potential of MAP4K4 in RCC therapy and support the development of an effective therapeutic strategy to target MAP4K4 by molecularly targeted approaches

ORGANISM(S): Homo sapiens

PROVIDER: GSE135105 | GEO | 2019/07/31

REPOSITORIES: GEO

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RNA-seq analysis of A498 cell line treated with siSETD2 or si-NC

Project description:the coordinated expression of SETD2-miRNAs-MAPK/JNK may be predictive of poor prognostic in patients with RCC. Our findings also emphasize the therapeutic potential of MAP4K4 in RCC therapy and support the development of an effective therapeutic strategy to target MAP4K4 by molecularly targeted approaches.

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SETD2 loss and ATR inhibition synergistically promote cGAS signaling and immunotherapy response in renal cell carcinoma

Project description:Immune checkpoint blockade (ICB) demonstrates durable clinical benefit only in a minority of renal cell carcinoma (RCC) patients. Identifying molecular features that determine response and developing approaches to enhance the response remain an urgent clinical need. Here we found that, in multiple RCC cell lines, targeting the ATR-CHK1 axis with pharmacological inhibitors increased cytosolic DNA accumulation, activated the cGAS-IRF3-dependent cytosolic DNA sensing pathway, and resulted in the inflammatory cytokine expression. SETD2 mutated RCC cell lines or tumor samples were associated with preferential ATR-CHK1 activation over ATM-CHK2 activation. SETD2 knockdown promoted the cytosolic DNA sensing pathway and conferred greater sensitivity in response to ATR-CHK1 inhibition. In murine Renca tumors, Setd2 knockdown and ATR inhibitor VE822 synergistically promoted cytosolic DNA sensing pathway, immune cell infiltration, and immune checkpoint protein expression. Setd2 deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or in combination with VE822 than Setd2 proficient tumors. SETD2 mutations were associated with a higher response rate and prolonged overall survival in ICB-treated RCC patients, but not in non-ICB-treated RCC patients. This study provides a mechanism-based guidance to develop more personalized combination therapy regimens for RCC patients with SETD2 mutations.

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SETD2-mediated loss of a panel of miRNAs determines MAPK/JNK signaling pathway activation and multidrug resistance in renal cell carcinoma

Project description:SETD2-mediated loss of a panel of miRNAs determines MAPK/JNK signaling pathway activation and multidrug resistance in renal cell carcinoma

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Dual Inhibition of DNA methylation and PARP Increases Anti-tumor Efficacy in SETD2 Deficient Kidney Cancer

Project description:Purpose: SETD2 deficiency, a driving force of depleted levels of H3K36me3 due to impaired methyltransferase activity, plays an important role in diverse forms of cancer, most notably in aggressive and metastatic clear cell renal cell carcinomas (ccRCC). Developing novel treatment schema targeting SETD2-compromised cancer cells are urgently needed. Methods: Human kidney cancer cell lines with or without SETD2 deficiency were treated with a DNA Hypomethylating Agent (HMA), a poly(ADP-ribose) polymerase inhibitor (PARPi), and both (HMA + PARPi) in combination in both in vitro and in vivo settings. Cell inhibition, Comet, flow cytometry, western blot, and RNA-sequencing (RNA-seq) gene expression assays as well as bioinformatic analyses were performed to explore the underlying mechanism action. Results: By taking advantage of involvement of SETD2 in DNA methylation and DNA repair, we found the combination treatment of an HMA (5-Aza-CdR/DAC) and a PARPi (Talazoparib/BMN-673) generated increased cytotoxicity in in vitro SETD2-deficient RCC cell lines than in SETD2-proficient cell lines. Furthermore, our results also demonstrate synergetic anti-tumor effects in SETD2 deficiency RCC cell lines when treated with DAC and BMN-673 that include apoptotic induction, increased DNA damage, insufficient DNA damage repair, upregulation of immune responses by STING and transposable elements (TEs), as well as increased genomic instability. Finally, the combination treatment for SETD2-deficient RCCs was also validated using in vivo mouse models. Conclusion: SETD2 deficiency creates a vulnerable epigenetic status to generate efficacious anti-tumor effects via the combination treatment of DAC and BMN-673 in human and mouse RCC systems, making it a precise medicine-based approach for SETD2-compromised cancers.

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents [methylation]

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Proteomics analysis on SETD2 loss induced ccRCC formation

Project description:Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain–containing 2 (SETD2) has been identified as an important tumor suppressor gene in ccRCC. However, the role of SETD2 in tumorigenesis during the transition from PKD to ccRCC remains largely unexplored. Herein, we performed metabolomics, lipidomics, transcriptomics and proteomics with SETD2 loss induced PKD-ccRCC transition mouse model. To characterize biological responses triggered by SETD2 deletion during PKD-ccRCC transition at the protein level, we conducted global proteomics studies.

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Chromatin landscape analysis of ccRCC cell line upon SETD2 rescue [ATACseq_JHRCC12]

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