SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways

Yuan, Huairui; Han, Ying; Wang, Xuege; Ni, Li; Liu, Qiuli; Yin, Yuye; Wang, Hanling; Pan, Lulu; Li, Li; Song, Kun; Qiu, Tong; Pan, Qiang; Chen, Qilong; Zhang, Guoying; Zang, Yi; Tan, Minjia; Zhang, Jian; Li, Qintong; Wang, Xiaoming; Jiang, Jun; Qin, Jun

doi:10.1016/j.ccell.2020.05.022

Cited by 131 publications

(118 citation statements)

References 81 publications

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“…Many methyltransferases are known to have multiple targets 16 . Recently, SETD2 has similarly been shown to methylate multiple proteins, including alpha-tubulin 20 , Signal transducer and activator of transcription 1 (STAT1) 21 , and Enhancer of zeste homolog 2 (EZH2) 22 . Thus, we sought to perform a systems-wide analysis of SETD2- dependent changes to the tumor proteome.…”

Section: Introductionmentioning

confidence: 99%

SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

Hapke

Venton

Rose

et al. 2020

Preprint

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SET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. To explore SETD2-dependent regulation of the kidney cancer proteome, we performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells. We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors. Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymetic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.

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Section: Introductionmentioning

confidence: 99%

SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

Hapke

Venton

Rose

et al. 2020

Preprint

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“…In our patient, we observed somatically acquired alterations in three histone lysine N-methyltransferase genes, including a missense mutation of SETD2, whole-gene loss of SETD8 (KMT5A), and deletion in KMT2C. It has recently been shown that SETD2-mediated H3K36me3 down-regulates EZH2-catalyzed H3K27me3 chromatin repression and that SETD2 deficiency promotes the development of metastatic prostate cancer (Yuan et al 2020). Similarly, SETD8 reduces EZH2-mediated cell proliferation, and reduction in SETD8 activity promotes oncogenesis (LeFave et al 2015).…”

Section: Discussionmentioning

confidence: 74%

Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance

Pandya

Shah

Kaplan

et al. 2021

Cold Spring Harb Mol Case Stud

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Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2 , are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.

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“…Among the 396 genes obtained in multivariate regression analysis, many genes have been extensively studied. For example, EZH2 , a methyltransferase, is closely related to tumor metastasis and proliferation ( 29 , 30 ). TNC , an extracellular matrix protein, plays an important role in tumor cell invasion and metastasis ( 31 , 32 ).…”

Section: Resultsmentioning

confidence: 99%

Identification of Key Functional Gene Signatures Indicative of Dedifferentiation in Papillary Thyroid Cancer

et al. 2021

Front. Oncol.

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Background: Differentiated thyroid cancer (DTC) is the most common type of thyroid cancer. Many of them can relapse to dedifferentiated thyroid cancer (DDTC) and exhibit different gene expression profiles. The underlying mechanism of dedifferentiation and the involved genes or pathways remained to be investigated.Methods: A discovery cohort obtained from patients who received surgical resection in the Fudan University Shanghai Cancer Center (FUSCC) and two validation cohorts derived from Gene Expression Omnibus (GEO) database were used to screen out differentially expressed genes in the dedifferentiation process. Weighted gene co-expression network analysis (WGCNA) was constructed to identify modules highly related to differentiation. Gene Set Enrichment Analysis (GSEA) was used to identify pathways related to differentiation, and all differentially expressed genes were grouped by function based on the GSEA and literature reviewing data. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to control the number of variables in each group. Next, we used logistic regression to build a gene signature in each group to indicate differentiation status, and we computed receiver operating characteristic (ROC) curve to evaluate the indicative performance of each signature.Results: A total of 307 upregulated and 313 downregulated genes in poorly differentiated thyroid cancer (PDTC) compared with papillary thyroid cancer (PTC) and normal thyroid (NT) were screened out in FUSCC cohort and validated in two GEO cohorts. WGCNA of 620 differential genes yielded the seven core genes with the highest correlation with thyroid differentiation score (TDS). Furthermore, 395 genes significantly correlated with TDS in univariate logistic regression analysis were divided into 11 groups. The areas under the ROC curve (AUCs) of the gene signature of group transcription and epigenetic modification, signal and substance transport, extracellular matrix (ECM), and metabolism in the training set [The Cancer Genome Atlas (TCGA) cohort] and validation set (combined GEO cohort) were both >0.75. The gene signature based on group transcription and epigenetic modification, cilia formation and movement, and proliferation can reflect the patient's disease recurrence state.Conclusion: The dedifferentiation of DTC is affected by a variety of mechanisms including many genes. The gene signature of group transcription and epigenetic modification, signal and substance transport, ECM, and metabolism can be used as biomarkers for DDTC.

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SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways

Abstract: Highlights d SETD2-mediated EZH2-K735me1 licenses EZH2 destruction to impede PCa metastasis d Cancer-associated SETD2 mutation (R1523H) disrupts SETD2-EZH2 interaction d Metformin treatment might combat EZH2-high PCa by stimulating SETD2 expression

Cited by 131 publications

References 81 publications

SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma

Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance

Identification of Key Functional Gene Signatures Indicative of Dedifferentiation in Papillary Thyroid Cancer

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