Distinct Regulation of EZH2 and its Repressive H3K27me3 Mark in Polyomavirus-Positive and-Negative Merkel Cell Carcinoma

被引：7

作者：

Durand, Marie-Alice ^{[1
]}

Mouchard, Alice ^{[1
,2
]}

Durand, Laurine ^{[1
]}

Esnault, Clara ^{[1
]}

Berthon, Patricia ^{[1
]}

Tallet, Anne ^{[3
]}

Le Corre, Yannick ^{[4
]}

Hainaut-Wierzbicka, Ewa ^{[5
]}

Blom, Astrid ^{[6
,7
]}

Saiag, Philippe ^{[6
,7
]}

Beneton, Nathalie ^{[8
]}

Bens, Guido ^{[9
]}

Nardin, Charlee ^{[1
,11
]}

Aubin, Francois ^{[1
,11
]}

Dinulescu, Monica ^{[1
,12
]}

Collin, Christine ^{[3
,10
]}

Fromont-Hankard, Gaelle ^{[13
]}

Cribier, Bernard ^{[1
,10
,14
]}

Laurent-Roussel, Sara ^{[1
,15
]}

Cokelaere, Kristof ^{[16
]}

Houben, Roland ^{[17
]}

Schrama, David ^{[17
]}

Peixoto, Paul ^{[18
,19
]}

Hervouet, Eric ^{[18
,19
]}

Bachiri, Kamel ^{[20
]}

Kantar, Diala ^{[20
]}

Coyaud, Etienne ^{[20
]}

Guyetant, Serge

Samimi, Mahtab ^{[1
,2
]}

Touze, Antoine ^{[1
]}

Kervarrec, Thibault ^{[1
,13
,21
]}

机构：

[1] Univ Tours, Team Biol Infect Polyomavirus, ISP UMR 1282, INRAE, Tours, France

[2] Univ Tours, Dept Dermatol, CHRU Tours, Chambray Les Tours, France

[3] Univ Tours, CHU Tours, Platform Somat Tumor Mol Genet, Tours, France

[4] LUNAM Univ, CHU Angers, Dept Radiol, Angers, France

[5] Univ Poitiers, Dermatol Dept, CHU Poitiers, Poitiers, France

[6] Ambroise Pare Hosp, Dept Gen & Oncol Dermatol, CARADERM Network, Boulogne Billancourt, France

[7] Paris Saclay Univ, Univ Versailles St Quentin En Yvelines, Res Unit EA 4340, Boulogne Billancourt, France

[8] Univ Le Mans, Dermatol Dept, CHU Mans, Le Mans, France

[9] CHR Orleans, Dermatol Dept, Orleans, France

[10] CHU Besancon, Dermatol, Besancon, France

[11] Univ Bourgogne Franche Comte, INSERM 1098, Besancon, France

[12] CHU Rennes, Inst Dermatol Grand Ouest IDGO, Dermatol Dept, Rennes, France

[13] Univ Tours, CHU Tours, Pathol Dept, Tours, France

[14] Univ Strasbourg, Dermatol Dept, CHU Strasbourg, Strasbourg, France

[15] Natl Dermatopathol Ctr, Paris, France

[16] Reg Hosp Jan Yperman, Pathol Dept, Ieper, Belgium

[17] Univ Hosp Wurzburg, Dept Dermatol Venerol & Allergol, Wurzburg, Germany

[18] Univ Bourgogne Franche Comte, INSERM, EFS BFC, UMR RIGHT 1098, Besancon, France

[19] Univ Bourgogne Franche Comte, EPIgenet & GENe Express Tech Platform EPIGENExp, Besancon, France

[20] Univ Lille, CHU Lille, Prote Reponse Inflammatoire Spectrometrie Masse PR, Inserm,U1192,Dept Biol, Lille, France

[21] CHRU Tours, Hop Trousseau, Dept Pathol, F-37044 Tours, France

来源：

JOURNAL OF INVESTIGATIVE DERMATOLOGY | 2023年 / 143卷 / 10期

关键词：

OPEN-LABEL; EXPRESSION; TAZEMETOSTAT; ASSOCIATION; CANCER;

D O I：

10.1016/j.jid.2023.02.038

中图分类号：

R75 [皮肤病学与性病学];

学科分类号：

100206 ;

摘要：

Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus positive than virus-negative tumors (P 1/4 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and-positive MCC.

引用

页码：1937 / 1946.e7

页数：17

共 60 条

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