《自然》子刊：研究发现脑肿瘤治疗新靶向

编辑翻译：奇奇

译文校对：菁菁

本文献发表在2021年3月最新的《自然通讯》（NatureC ommunications）上。文献中弗吉尼亚联邦大学（VCU）梅西癌症中心研究员发现，导致脑肿瘤细胞中胆固醇异常调节的基因有望成为未来癌症药物的新靶点。

大多数人都会将胆固醇水平与心脏健康联系起来，然而胆固醇水平也是脑肿瘤生长和扩散的一个关键因素。弗吉尼亚联邦大学（VCU）梅西癌症中心研究员黄素云博士最近发现了脑肿瘤细胞中胆固醇异常调节，并表明导致胆固醇失调的基因可能成为未来药物的靶点。

多形性胶质母细胞瘤（GBM）是最为常见的、最具侵袭性的脑肿瘤，其患者医学平均生存期为14个月。找到新的、有效的治疗方法迫在眉睫，这也促使梅西癌症生物学研究项目的黄教授详细研究了很多导致脑肿瘤发展的基本因素，像基因、蛋白质、酶以及其他细胞成分。她的研究展现了一种生物“路线图”，也揭示了之前没有发现的基因功能。

黄博士的最新研究发表在《自然通讯》上，她精准定位了YTHDF2基因，该基因是导致GBM发展和生长的链条关键点。YTHDF2的作用过程依赖于EGFR的运转，EGFR是另一种被公认为推动癌症发展的基因。

黄博士同时也是VCU医学院人类和分子遗传学系的教授。她说：“这些研究发现令人兴奋，因为我们可以通过使用YTHDF2小分子靶向抑制YTHDF2的表达，以控制胶质细胞肿瘤的生长与扩散。我们的实验还表明，我们可以通过阻断YTHDF2的表达来阻止脑肿瘤细胞的形成与生长。因此，这也可以成为药物开发的有力靶点。”

EGFR在许多包括GBM的侵略性癌症中经常过度活跃。黄博士的研究团队发现，EGFR促使TYHDF2过度表达，然后通过降解LX Rα和HIVEP2基因来维持胆固醇水平的增高，以推动GBM细胞的侵入性生长和发展。LXRα可以调节细胞内的胆固醇水平，而HIVEP2则参与脑组织的发育。

黄博士的研究是第一次描述这种细胞信号级联的研究，它帮助填补了导致GBM的“路线图”的重要部分。研究首次表明了N6-甲基腺苷（m6A）在脑瘤发展和胆固醇代谢中的作用。m6A是一种DNA修饰，存在于几乎所有以细胞为基础的生命中。黄博士的团队发现YTHDF2表达的增加导致LXRα和HIVEP2的mRNA中m6A修饰，这种修饰抑制了它们的功能。

接下来，黄博士和她的伙伴计划评估不同的YTHDF2抑制因素，并将它们应用到实验室和动物模型上。

黄博士说：“EGFR抑制和胆固醇调节都是有发展前景的GBM治疗策略。我们的研究提供了一种令人兴奋的新方法，该方法可能让这些策略共同调控和治疗GBM。”

英语原文

Researcher Finds New Strategy for Fighting Brain Cancer

Most people relate cholesterol to heart health, but it is also a critical component in the growth and spread of brain cancer. VCU Massey Cancer Center researcher Suyun Huang, Ph.D., recently discovered how cholesterol becomes dysregulated in brain cancer cells and showed that the gene responsible for it could be a target for future drugs.

The mean survival of patients with the most common and aggressive type of brain cancer, glioblastoma multiforme (GBM), is 14 months. The need to find new, effective treatments is urgent and has driven Huang, a member of the Cancer Biology research program at Massey, to detail the workings of numerous genes, proteins, enzymes and other cellular componentsthat contribute to brain cancer growth. Her studies are revealing a biological "roadmap" showing previously unknown functions of genes.

Huang's most recent study, published in the journal Nature Communications, pinpoints a gene called YTHDF2 as a crucial link in a chain leading to the development and growth of GBM. It works through aprocess set in motion by another gene with a well-established reputation for driving cancer progression, EGFR.

"These findings are exciting becausewe can potentially target YTHDF2 expression by using YTHDF2 small molecule inhibitors to control glioblastoma tumor growth and spread," says Huang, who is also a professor in the Department of Human and Molecular Genetics at VCU School of Medicine. "Our experiments also showed that we can stop the formation and growth of brain cancer cells by blocking YTHDF2 expression, so itcould also be a powerful target for drug development."

EGFR is frequently overactivated in many aggressive cancers, including GBM. Huang's team found that EGFR drives the overexpression of TYHDF2, whichthen sustains increased cholesterol levels for the invasive growth and development of GBM cells through a process that degrades the LXRα and HIVEP2 genes. LXRα is known to regulate cholesterol levels within cells and HIVEP2 is involved in the development of brain tissue.

Huang's study is the first to describe thiscell signaling cascade, and it helps fill in important parts of the "roadmap" leading to GBM. It is also the first study to show that N6-methyladenosine (m6A), a DNA modification found in nearly all cell-basedlife forms, plays a role in brain tumor growth and cholesterol metabolism. Huang's team found that the increase in YTHDF2 expression caused m6A modifications in the mRNA of LXRα and HIVEP2, which inhibited their functions.

Next, Huang and her collaborators plan to evaluate different YTHDF2 inhibitors and establish their effects in lab andanimal models.

"EGFR inhibition and cholesterol regulation are both promising strategies for GBM treatment," says Huang. "Our study offers an exciting new approach that could potentially work hand-in-hand with these strategies to regulate and treat GBM."

参考文献

Runping Fang et al, EGFR/SRC/ERK-stabilizedYTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma,Nature Communications (2021). DOI: 10.1038/s41467-020-20379-7

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