BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood.METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and tran-scriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas.RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozy-gous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1-and Tdg- mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene in-flammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromo-somal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/ interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activ-ities. These mice represent a model of CIMP CRC.

TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype / Tricarico, Rossella; Madzo, Jozef; Scher, Gabrielle; Cohen, Maya; Jelinek, Jaroslav; Maegawa, Shinji; Nagarathinam, Rajeswari; Scher, Carly; Chang, Wen-Chi; Nicolas, Emmanuelle; Slifker, Michael; Zhou, Yan; Devarajan, Karthik; Cai, Kathy Q; Kwok, Tim; Nakajima, Pamela; Xu, Jinfei; Mancuso, Pietro; Doneddu, Valentina; Bagella, Luigi; Williams, Riley; Balachandran, Siddharth; Maskalenko, Nicholas; Campbell, Kerry; Ma, Xueying; Cañadas, Israel; Viana-Errasti, Julen; Moreno, Victor; Valle, Laura; Grivennikov, Sergei; Peshkova, Iuliia; Kurilenko, Natalia; Mazitova, Aleksandra; Koltsova, Ekaterina; Lee, Hayan; Walsh, Martin; Duttweiler, Reuben; Whetstine, Johnathan R; Yen, Timothy J; Issa, Jean-Pierre; Bellacosa, Alfonso. - In: GASTROENTEROLOGY. - ISSN 1528-0012. - 164:6(2023), pp. 921-936.e1. [10.1053/j.gastro.2023.01.039]

TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype

Doneddu, Valentina;Bagella, Luigi;Bellacosa, Alfonso
2023-01-01

Abstract

BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood.METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and tran-scriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas.RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozy-gous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1-and Tdg- mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene in-flammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromo-somal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/ interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activ-ities. These mice represent a model of CIMP CRC.
2023
TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype / Tricarico, Rossella; Madzo, Jozef; Scher, Gabrielle; Cohen, Maya; Jelinek, Jaroslav; Maegawa, Shinji; Nagarathinam, Rajeswari; Scher, Carly; Chang, Wen-Chi; Nicolas, Emmanuelle; Slifker, Michael; Zhou, Yan; Devarajan, Karthik; Cai, Kathy Q; Kwok, Tim; Nakajima, Pamela; Xu, Jinfei; Mancuso, Pietro; Doneddu, Valentina; Bagella, Luigi; Williams, Riley; Balachandran, Siddharth; Maskalenko, Nicholas; Campbell, Kerry; Ma, Xueying; Cañadas, Israel; Viana-Errasti, Julen; Moreno, Victor; Valle, Laura; Grivennikov, Sergei; Peshkova, Iuliia; Kurilenko, Natalia; Mazitova, Aleksandra; Koltsova, Ekaterina; Lee, Hayan; Walsh, Martin; Duttweiler, Reuben; Whetstine, Johnathan R; Yen, Timothy J; Issa, Jean-Pierre; Bellacosa, Alfonso. - In: GASTROENTEROLOGY. - ISSN 1528-0012. - 164:6(2023), pp. 921-936.e1. [10.1053/j.gastro.2023.01.039]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/317129
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