PNAS：自噬帮肿瘤抵抗化疗

　　

生物通报道：神经母细胞瘤（Neuroblastoma）是一种常见的儿童恶性实体瘤，起源于胚胎神经系统的细胞。传统化疗往往不能有效治疗高侵袭性的神经母细胞瘤，要开发新的有效疗法，就必需先理解这类肿瘤的抗性机制。

德国癌症研究中心DKFZ和海德堡大学附属医院的科学家们，在Olaf Witt教授的带领下进行研究，发现一种组蛋白去乙酰化酶是神经母细胞瘤抵抗化疗的关键，文章发表在美国国家科学院院刊PNAS杂志上。这项研究为人们带来了克服神经母细胞瘤抗性的希望，将帮助科学家们开发出更有效的治疗方法。

研究人员指出，组蛋白去乙酰化酶HDAC可以通过多种途径，促进神经母细胞瘤的侵袭性。Dr. Ina Oehme及其同事对高危神经母细胞瘤进行研究，寻找与化疗敏感性有关的HDAC家族成员。他们发现，有些高危肿瘤中的HDAC10产量较少，而这些肿瘤对化疗更为敏感。

随后，研究人员在高侵袭性的神经母细胞瘤中，抑制HDAC10的活性，并用化疗试剂阿霉素（doxorubicin）处理细胞。在正常情况下，神经母细胞瘤在阿霉素的作用下，会启动自噬程序。自噬是细胞内部元件的回收再利用机制，这一古老的生物学程序，可以帮助细胞在饥饿环境下生存。高侵袭性的癌细胞能通过自噬，克服细胞毒素带来的压力。

研究显示，在缺乏功能性HDAC10的神经母细胞瘤中，化疗成功破坏了细胞的自噬过程，使这些细胞重新恢复了对抗癌药物的敏感性。为了检验这一结果，研究人员又在神经母细胞瘤中，增强HDAC10基因的活性，结果使细胞对化疗产生了抵抗。

“在高危神经母细胞瘤中，HDAC10对细胞自噬和化疗抗性具有关键性作用，”Olaf Witt总结道。“研究显示，晚期肿瘤的HDAC10水平可以作为抗性指标，高水平的HDAC10意味着肿瘤将对化疗产生抵抗。能特异性抑制HDAC10的化合物，将有望成为更有效的抗癌药物，帮助人们治疗对化疗产生抗性的神经母细胞瘤。”

 

（生物通编辑：叶予）

生物通推荐原文摘要：

Histone deacetylase 10 promotes autophagy-mediated cell survival

Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.