Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy

Xu, Yanping; Lv, Lei; Liu, Ying; Smith, Matthew D.; Li, Wencai; Tan, Xianming; Cheng, Meng; Li, Zhijun; Bovino, Michael; Aubé, Jeffrey; Xiong, Yue

doi:10.1172/jci129317

Cited by 166 publications

(151 citation statements)

References 74 publications

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“…4A), providing further support for the function of USP15 in IFN signaling. Among these IFN--induced genes whose expression was also down-regulated by Tet2 KO are Cxcl9, Cxcl10, and Cxcl11, which are often referred to as T H 1-type chemokines and are consistent with our previous discovery (20). In addition to DNA demethylation, several other epigenetic modification enzymes have also been previously linked to the regulation of T H 1-type chemokine expression and tumor immunity, including PRC2 complex (e.g., EZH2), DNMTs, and SWI/SNF (switching defective/sucrose non-fermenting) complex (e.g., ARID1A) (55,56).…”

Section: Discussionsupporting

confidence: 89%

“…We next determined whether USP15 can change the expression of TET2 target genes. We previously reported the function of TET2 in mediating interferon- (IFN-) signaling (20). We therefore determined gene expression in WT, Tet2, and Usp15 KO B16 melanoma HEK293T cells were singularly transfected with Flag-TET2 or cotransfected with Flag-TET2 and Myc-DCAF1 or Myc-DCAF1(RARA) mutant.…”

Section: Usp15 and Tet2 Oppositely Regulate Genes Involved In Multiplmentioning

confidence: 99%

“…TET genes are rarely mutated or significantly reduced in expression in solid tumors (20). However, the activity of TET enzymes, as determined by its enzymatic product, 5hmC, is significantly decreased in a wide range of solid tumors lacking mutation targeting TET genes (21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

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USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

et al. 2020

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TET2 DNA dioxygenase is frequently mutated in human hematopoietic malignancies and functionally inactivated in many solid tumors through a nonmutational mechanism. We recently found that TET2 mediates the interferon-JAK-STAT pathway to stimulate chemokine expression and tumor infiltration of lymphocytes (TILs). TET2 is monoubiquitylated at K1299, which promotes its activity. Here, we report that USP15 is a TET2 deubiquitinase and inhibitor. USP15 catalyzes the removal of K1299-linked monoubiquitin and negatively regulates TET2 activity. Gene expression profiling demonstrates that TET2 and USP15 oppositely regulate genes involved in multiple inflammatory pathways, and TET2 is a major target of USP15 function. Deletion of Usp15 in melanoma stimulates chemokine expression and TILs in a TET2-dependent manner, leading to increased response to immunotherapy and extended life span of tumor-bearing mice. These results reveal a previously unknown regulator of TET2 activity and suggest USP15 as a potential therapeutic target for immunotherapy of solid tumors.

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Section: Discussionsupporting

confidence: 89%

Section: Usp15 and Tet2 Oppositely Regulate Genes Involved In Multiplmentioning

confidence: 99%

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USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

et al. 2020

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“…Considering that 5mC and TET2 are both closely related to the regulation of DNA methylation, it might be reasonable to hypothesize that 5mC and TET2 also participate in the etiology of the existence or progression of precancerous lesion. In this study, we found that 5hmC and TET2 expressions were both negatively correlated with the histological classification, and here were several possible explanations to the results in our study: (a) 5hmC and TET2 might prevent the formation or repress the progression of breast precancerous lesion via modulating stemness or other related processes, which still need more in vivo and in vitro experiments to validate; (b) 5hmC and TET2 might also inhibit precancerous lesion development and progression via similar mechanism by which they suppress the cancer progression, for instance, repressing malignant behaviors of cancer cells by mediating multiple oncogenic signaling pathways . However, we did not find a statistically significant correlation between 5mC and histopathological classification, which may be due to the dual role of 5mC in cancer pathogenesis found in other cancers, or a relatively small sample size …”

Section: Discussionmentioning

confidence: 51%

“…These results suggest that 5hmC functions as a regulator repressing tumorigenesis. As to TET2, it has been reported to enhance the immunity and treatment efficacy of anti‐PD‐L1 agents in human colon cancer by modulating the interferon γ (IFNγ)‐JAK‐STAT signaling pathway . And a lack of TET2 in B cells contributes to germinal center hyperplasia, damage in class switch recombination, blocking of plasma cell differentiation, and a B cell lymphomagenesis .…”

Section: Discussionmentioning

confidence: 99%

Values of 5mC, 5hmC, and TET2 for identifying the presence and progression of breast precancerous lesion

Zhang

Jin

Zhang

et al. 2019

Clinical Laboratory Analysis

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: This study aimed to evaluate the correlations of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and ten-eleven translocation enzyme 2 (TET2) expressions in lesion tissue with histological classification of breast precancerous lesion. Methods:Eighty-three patients with breast ductal intraepithelial neoplasia (DIN), 20 patients with breast ductal carcinoma in situ with microinvasion (DCIS-MI), and 10 patients with invasive breast cancer were included. Histological classification of the DIN patients was classified as DIN1A, DIN1B, DIN1C, DIN2, and DIN3. 5mC, 5hmC, and TET2 expressions in lesion tissues from biopsy were assessed by immunohistochemistry (IHC) assay.Results: 5hmC and TET2 were negatively associated with histological classification as validated by both IHC score and IHC semi-quantification expression grades in total patients (all P < .05); however, no correlation of 5mC with histological classification was found (all P > .05). 5mC (P = .004) was negatively but 5hmC (P < .001) was positively correlated with TET2, while no association of 5mC with 5hmC was discovered in total patients (P = .078). In addition, 5mC was positively associated with ER expression in total patients (P = .040). In subgroups, 5mC was negatively correlated with 5hmC in DIN1C patients (P = .023) and invasive cancer patients (P = .044), and 5mC was negatively associated with TET2 in DIN1B patients (P = .004) as well as DCIS-MI patients (P = .003).Conclusion: 5hmC and TET2 have the potentials to serve as biomarkers that could assist in the identification of presence and progression of breast precancerous lesion. K E Y W O R D S5-methylcytosine, 5-hydroxymethylcytosine, biomarker, breast precancerous lesion, teneleven translocation enzyme 2 1 | INTRODUC TI ON Breast cancer, the most frequent cancer in women worldwide, attacks approximately 2 088 849 patients and results in roughly 626 679 related deaths in 2018. 1 Breast cancer is featured by the heterogeneous molecular subtypes, such as luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) enriched type, and basal-like breast cancer, which is closely related to the therapeutic decision-making and prognosis in clinical setting. 2 In Asia, an elevation of breast cancer incidence could be seen as a R E FE R E N C E S How to cite this article: Zhang Z, Jin Y, Zhang W, et al. Values of 5mC, 5hmC, and TET2 for identifying the presence and progression of breast precancerous lesion. J Clin Lab Anal.

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Rapid and Label‐Free Detection of 5‐Hydroxymethylcytosine in Genomic DNA Using an Au/ZnO Nanorods Hybrid Nanostructure‐Based Electrochemical Sensor

Bhat

Kim

Alam

et al. 2021

Adv Healthcare Materials

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Ten-eleven-translocation (TET) proteins modify DNA methylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Loss of 5hmC, a widely accepted epigenetic hallmark of cancers, is proposed as a biomarker for early cancer diagnosis and prognosis. Thus, precise quantification of 5hmC holds great potential for diverse clinical applications. DNAs containing 5mC or 5hmC display different adsorption affinity toward the gold surface, thus producing different electrochemical responses. Here a novel, label-free electrochemical sensor based on gold nanoparticles (Au NPs)/zinc oxide nanorods (ZnO NRs) nanostructure for the facile and real-time detection of 5hmC-enriched DNAs is reported. The hybrid structure is fabricated by the vertical hydrothermal growth of ZnO NRs onto indium tin oxide glass substrate, followed by the decoration of ZnO NRs with Au NPs via sputtering. Successful fabrication is confirmed by analyzing the morphology and chemical composition of the sensor. By coupling the fabricated sensor with cyclic voltammetry, its functionality in distinguishing genomic DNAs containing different levels of 5hmC is validated. Notably, the sensor device successfully and consistently detects 5hmC loss in primary hepatocellular carcinoma, compared to the normal tissues. Thus, the novel sensing strategy to assess DNA hydroxymethylation will likely find broad applications in early cancer diagnosis and prognosis evaluation.

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Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy

Cited by 166 publications

References 74 publications

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2

Values of 5mC, 5hmC, and TET2 for identifying the presence and progression of breast precancerous lesion

Rapid and Label‐Free Detection of 5‐Hydroxymethylcytosine in Genomic DNA Using an Au/ZnO Nanorods Hybrid Nanostructure‐Based Electrochemical Sensor

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