DNA高甲基化，由DNMT1和DNMT3A驱动，有利于肾上腺皮质癌的肿瘤免疫逃避，同时增加其恶性程度。
DNA hypermethylation driven by DNMT1 and DNMT3A favors tumor immune escape contributing to the aggressiveness of adrenocortical carcinoma.
发表日期：2023 Aug 02
作者：
Gwenneg Kerdivel, Floriane Amrouche, Marie-Ange Calmejane, Floriane Carallis, Juliette Hamroune, Constanze Hantel, Jérôme Bertherat, Guillaume Assié, Valentina Boeva
来源：
Epigenetics & Chromatin
摘要：
肾上腺皮质癌是肾上腺的一种罕见且侵袭性的内分泌癌症。在肾上腺皮质癌中，一种最近被描述的亚型，其特征为CpG岛甲基化表型（CIMP），被发现与尤其不良的预后相关。然而，CIMP的驱动因素尚不明确。此外，CIMP与肾上腺皮质癌患者不良临床结局之间的功能关系仍然模糊不清。在这里，我们展示了CIMP与增加的DNA甲基转移酶DNMT1和DNMT3A的表达相关联，其由基因拷贝数的增加和细胞过度增殖驱动。重要的是，我们证明了CIMP通过促进肿瘤免疫逃逸来促进肿瘤的侵袭性。这种效应可以至少部分地通过去甲基化剂5-azacytidine的治疗进行逆转。总的来说，我们的研究结果表明，联合应用去甲基化剂可能增强免疫疗法的功效，并可能成为高CIMP肾上腺皮质癌患者的一种新的治疗方法。© 2023作者。
Adrenocortical carcinoma is rare and aggressive endocrine cancer of the adrenal gland. Within adrenocortical carcinoma, a recently described subtype characterized by a CpG island methylator phenotype (CIMP) has been associated with an especially poor prognosis. However, the drivers of CIMP remain unknown. Furthermore, the functional relation between CIMP and poor clinical outcomes of patients with adrenocortical carcinoma stays elusive.Here, we show that CIMP in adrenocortical carcinoma is linked to the increased expression of DNA methyltransferases DNMT1 and DNMT3A driven by a gain of gene copy number and cell hyperproliferation. Importantly, we demonstrate that CIMP contributes to tumor aggressiveness by favoring tumor immune escape. This effect could be at least partially reversed by treatment with the demethylating agent 5-azacytidine.In sum, our findings suggest that co-treatment with demethylating agents might enhance the efficacy of immunotherapy and could represent a novel therapeutic approach for patients with high CIMP adrenocortical carcinoma.© 2023. The Author(s).