Multilevel Regulation of β-Catenin Activity by SETD2 Suppresses the Transition from Polycystic Kidney Disease to Clear Cell Renal Cell Carcinoma

Rao, Hanyu; Li, Xiaoxue; Liu, Min; Liu, Jing; Feng, Wenlong; Tang, Huayuan; Xu, Jin; Gao, Wei‐Qiang; Li, Li

doi:10.1158/0008-5472.can-20-3960

Cited by 20 publications

(37 citation statements)

References 54 publications

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“…This study systematically investigated SETD2 deficiency-caused ccRCC in vivo based on comprehensive analysis of multi-omics. We conducted proteomics, lipidomics and metabolomics datasets, meanwhile adopted transcriptomics data sourced from our published work 19 that was performed under exactly the same conditions as those of the current work. Our multi-omics analysis revealed various biological progression alters in mice with SETD2-deficient-caused ccRCC, including various metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

“…The array of tumor suppressor genes, which are mutated or inactivated in tumorigenesis, are reported to be involved in the alterations and perturbations of various metabolic events, including citrate cycle (TCA cycle), fatty acid biosynthesis, glycolysis, amino acid metabolism, carbohydrate absorption and modulation of pathways important for redox balance [14][15][16] . The typical phenotypic feature of ccRCC is the clear cell morphology, which is associated with excessive accumulation of lipids in the cytoplasm [17][18][19] . The specific excess accumulation of lipids during the progression from PKD to ccRCC needs to be further explored and clarified.…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: SETD2 deficiency promotes the transition from PKD to ccRCC by dysregulation of sphingomyelin metabolism

Zhang

Liu

et al. 2022

Preprint

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Clear cell renal cell carcinoma (ccRCC) is a malignant tumor with dysregulated lipid metabolism, and is highly incidental in polycystic kidney disease (PKD) patients. However, SETD2 is an important tumor suppressor gene in ccRCC generation, yet the underlying mechanisms, especially the effects of lipid metabolism, remain largely unexplored. Here, we revealed extensive and large-scale metabolic reprogramming events in a SETD2-deficient ccRCC mouse model by performing a multi-omics study comprising transcriptomics, proteomics, metabolomics, lipidomics and metabolic mass spectrometry imaging approaches. Our data unveiled dramatic alteration of fatty acid biosynthesis, glycerolipid metabolism, glycerophospholipid metabolism, tricarboxylic acid cycle (TCA), carbohydrate digestion and absorption, protein digestion and absorption and biosynthesis of amino acids, which eventually led to dysregulated sphingomyelin metabolism-related metabolic pathways. Clinically, we discovered that TCA and amino acid metabolism are positively associated with SETD2, while glycolysis, protein catabolic and lipids biosynthesis are negatively associated with SETD2. Mass spectrometry imaging of clinical ccRCC tissues revealed that SETD2 mutation is associated with upregulated sphingomyelin biosynthesis in human ccRCC. Our study provides a comprehensive resource of biological data to support future investigations of SETD2-deficient ccRCC, facilitating the development of metabolically targeted therapeutic modalities.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: SETD2 deficiency promotes the transition from PKD to ccRCC by dysregulation of sphingomyelin metabolism

Zhang

Liu

et al. 2022

Preprint

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“…In addition, our recent studies reported that SETD2 plays important roles in intestinal immunity, suppressing intestinal inflammation, maternal epigenome, genomic imprinting and embryonic development, bone marrow mesenchymal stem cell differentiation, sperm development, and V(D)J recombination in normal lymphocyte development. [23][24][25][26][27][28][29][30][31] Moreover, SETD2 loss led to pancreatic carcinogenesis through epigenetic dysregulation of Fbxw7. Based on the polycystic kidney disease (PKD) model caused by the oncogene MYC, SETD2 deficiency accelerates the transition from polycystic kidney disease (PKD) to RCC by regulating β-catenin activity on transcriptional and post-transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%

“…Our recent studies also reported that SETD2 plays important role in developmental areas and disease occurrence. [23][24][25][26][27][28][29][30][31] Notably, SETD2 deficiency accelerates the transition from polycystic kidney disease (PKD) to renal cell carcinoma (RCC) by regulating β-catenin activity. 31 However, the role of SETD2 in renal fibrosis remains still unknown.…”

Section: Introductionmentioning

confidence: 99%

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SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signaling pathway in the absence of VHL

Liu

Zhu

et al. 2022

Preprint

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Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. An important intrinsic cause of renal fibrosis is epigenetic alterations. SET domain containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalyzing H3K36 dimethylation to trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. Clinical data indicate that SETD2 is lowly expressed in patients with renal fibrosis. Here, we established genetically engineered mice with SETD2 and VHL deficiency. SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the TGF-β/Smad signaling pathway, thereby preventing the activation of the TGF-β/Smad signaling pathway. Deletion of SETD2 leads to reduced smad7 expression, which results in activation of the TGF-β/Smad signaling pathway and ultimately fibrosis in the absence of VHL. Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-β/Smad signaling pathway in renal fibrogenesis. Thus, our study provides innovative insights into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

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Tumor Cell‐Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis

et al. 2022

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Genetic and epigenetic alterations play central roles in shaping the immunosuppressive tumor microenvironment (TME) to evade immune surveillance. The previous study shows that SETD2‐H3K36me3 loss promotes KRAS‐induced pancreatic tumorigenesis. However, little is known about its role in remodeling the TME and immune evasion. Here, it is shown that SETD2 deficiency can reprogram neutrophils to an immunosuppressive phenotype, thereby promoting immune escape during pancreatic tumor progression. By comprehensive profiling of the intratumoral immune cells, neutrophils are identified as the subset with the most significant changes upon Setd2 loss. Setd2‐deficient pancreatic tumor cells directly enhance neutrophil recruitment and reprogramming, thereby inhibiting the cytotoxicity of CD8+ T cells to foster tumor progression. Mechanistically, it is revealed that Setd2‐H3K36me3 loss leads to ectopic gain of H3K27me3 to downregulate Cxadr expression, which boosts the PI3K‐AKT pathway and excessive expression of CXCL1 and GM‐CSF, thereby promoting neutrophil recruitment and reprogramming toward an immunosuppressive phenotype. The study provides mechanistic insights into how tumor cell‐intrinsic Setd2 deficiency strengthens the immune escape during pancreatic tumorigenesis, which may offer potential therapeutic implications for pancreatic cancer patients with SETD2 deficiency.

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Multilevel Regulation of β-Catenin Activity by SETD2 Suppresses the Transition from Polycystic Kidney Disease to Clear Cell Renal Cell Carcinoma

Cited by 20 publications

References 54 publications

WITHDRAWN: SETD2 deficiency promotes the transition from PKD to ccRCC by dysregulation of sphingomyelin metabolism

WITHDRAWN: SETD2 deficiency promotes the transition from PKD to ccRCC by dysregulation of sphingomyelin metabolism

SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signaling pathway in the absence of VHL

Tumor Cell‐Intrinsic SETD2 Deficiency Reprograms Neutrophils to Foster Immune Escape in Pancreatic Tumorigenesis

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