小柯机器人

近日，法国巴黎文理研究大学Céline Vallot及其研究小组发现，H3K27me3影响三阴性乳腺癌的化学耐受性。相关论文于2022年4月11日在线发表于国际学术期刊《自然—遗传学》。

通过监测表观基因组、转录组和单细胞的分辨率，研究人员表明抑制性组蛋白标记H3K27me3（组蛋白H3在第27位赖氨酸的三甲基化）在化疗开始时调节细胞命运。结果表明，在未受化疗的细胞中，持久性表达程序是以H3K4me3（组蛋白H3在第4位赖氨酸的三甲基化）和H3K27me3为基础的，而H3K27me3是其转录激活的锁。研究人员进一步证明，耗尽H3K27me3能增强癌细胞对化疗的耐受潜力。相反，在化疗的同时防止H3K27me3去甲基化会抑制向药物耐受状态的转变，并推迟体内肿瘤的复发。这些结果强调了染色质景观如何塑造癌细胞对初始治疗的反应潜力。

据介绍，对治疗有抵抗力的癌细胞的持续存在仍然是一个主要的临床挑战。在三阴性乳腺癌中，对化疗的抗性导致乳腺癌亚型中最高的复发风险。耐药状态似乎在很大程度上由非遗传特征定义，但对其基本机制了解甚少。

附：英文原文

Title: H3K27me3 conditions chemotolerance in triple-negative breast cancer

Author: Marsolier, Justine, Prompsy, Pacme, Durand, Adeline, Lyne, Anne-Marie, Landragin, Camille, Trouchet, Amandine, Bento, Sabrina Tenreira, Eisele, Almut, Foulon, Sophie, Baudre, La, Grosselin, Kevin, Bohec, Mylne, Baulande, Sylvain, Dahmani, Ahmed, Sourd, Laura, Letouz, Eric, Salomon, Anne-Vincent, Marangoni, Elisabetta, Peri, Lela, Vallot, Cline

Issue&Volume: 2022-04-11

Abstract: The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages with single-cell resolution, we show that the repressive histone mark H3K27me3 (trimethylation of histoneH3 at lysine27) regulates cell fate at the onset of chemotherapy. We report that a persister expression program is primed with both H3K4me3 (trimethylation of histoneH3 at lysine4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation. We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy. Conversely, preventing H3K27me3 demethylation simultaneously to chemotherapy inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo. Our results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy.

DOI: 10.1038/s41588-022-01047-6

Source: https://www.nature.com/articles/s41588-022-01047-6

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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