ZMYND8

Researchers have uncovered a gene that is overexpressed in mutated IDH1. Studies in human cells and a novel mouse model both show that this gene, called ZMYND8, plays a critical role in the radiation resistance. When they knocked down the gene, the glioma cells became responsive to radiation treatment. It's a good news, bad news story. Patients whose brain tumors have a mutated enzyme called IDH1 typically live longer than those without the mutation. But even as these tumors are initially less aggressive, they always come back. A key reason: The tumors are resistant to radiation treatment and are invasive. In a new study, researchers at the University of Michigan Rogel Cancer Center uncovered a gene that is overexpressed in mutated IDH1. Studies in human cells and a novel mouse model both show that this gene, called ZMYND8, plays a critical role in the radiation resistance. When they knocked down the gene, the glioma cells became responsive to radiation treatment. "These tumors almost always recur, and when they do, the tumors are much more aggressive. This finding gives us a new therapeutic avenue to treat these patients. It's a very promising and novel therapeutic target," said Maria G. Castro, Ph.D., R.C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine. Castro is senior author on the study, published in Clinical Cancer Research, a journal of the American Association for Cancer Research. The researchers used two cell cultures obtained from surgical biopsies of patients with mutated IDH1 glioma. Cells were treated with an inhibitor designed to block a metabolite produced by the mutated IDH1. From there, they screened the RNA and found a gene called ZMYND8. "After treating with the mIDH1 inhibitor, we found this gene, ZMYND8, was significantly downregulated. It's overexpressed in mutant IDH1 glioma cells, but when you treat the cells with an inhibitor, ZMYND8 protein expression goes down. And when this gene goes down, the cells become radiosensitive," said study first author Stephen V. Carney, a Cancer Biology graduate student in the Castro/Lowenstein Lab. ZMYND8 is known to be a regulator of DNA damage response. Radiation therapy works by damaging DNA. When ZMYND8 protein expression is high, researchers saw radiation resistance. When ZMYND8 was knocked out, the radiation led to DNA damage and increased glioma cell death. The researchers also developed a new mouse model of mutated IDH1 glioma, which confirmed that knocking out ZMYND8 sensitized the tumors to radiation therapy, leading to increased survival. "ZMYND8 contributes to the survival of mutant IDH1 glioma in response to radiation. Our study shows that we now have a new way of treating these tumors by using mRNA-based therapeutics in which we can downregulate the expression of ZMYND8 to render the cells radiosensitive," said study author Pedro R. Lowenstein, M.D., Ph.D., Richard C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine. The researchers also combined ZMYND8 knockdown with other cancer drugs, such as PARP and HDAC inhibitors. They found these other drugs synergized to make the cells more responsive to radiation, suggesting potential for combination therapy for patients with mutant IDH1 glioma. More research is needed, but Castro envisions working with colleagues at the U-M Biointerfaces Institute to design RNA-based inhibitors to target ZMYND8, which could be delivered using nanoparticles specially designed to cross the challenging blood-brain barrier. It's a technique they've already tested in previous research. Additional authors:Kaushik Banerjee, Anzar Mujeeb, Brandon Zhu, Santiago Haase, Maria L. Varela, Padma Kadiyala, Claire E. Tronrud, Ziwen Zhu, Devarshi Mukherji, Preethi Gorla, Yilun Sun, Rebecca Tagett, Felipe J. Nunez, Maowu Luo, Weibo Luo, Mats Ljungman, Yayuan Liu, Ziyun Xia, Anna Schwendeman, Tingting Qin, Maureen A. Sartor, Joseph F. Costello, Daniel P. Cahill Funding for this work is from National Institutes of Health grants R37-NS094804, R01-NS105556, R01-NS122536, R01-NS122165, R01-NS124167, R21-NS123879, R01-NS076991, R01-NS082311, R01-NS096756, R01-NS122234, R01-CA243916, T32-CA009676, PA18-906, the Pediatric Brain Tumor Foundation, Leah's Happy Hearts Foundation, Ian's Friends Foundation, Chad Tough Foundation, Smiles for Sophie Forever Foundation. This work was supported by these Rogel Cancer Center Shared Resources: Cancer Data Science, Experimental Irradiation, Flow Cytometry, Preclinical Molecular Imaging, Single Cell Spatial Analysis, Tissue and Molecular Pathology.

来自德克萨斯大学西南医学中心等机构的科学家们通过研究在乳腺癌中识别出了一种致病性的信号通路，其或有望为开发治疗这种常见乳腺癌的新型疗法提供潜在的新型靶点。 27-羟基胆固醇（27-HC,27-Hydroxycholesterol）是增加乳腺癌进展风险最丰富的氧甾酮(oxysterol)，然而目前研究人员并不清楚27-HC代谢的表观遗传学调节以及其在乳腺肿瘤发生中所扮演的关键角色。近日，一篇发表在国际杂志Science Advances上题为“ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells”的研究报告中，来自德克萨斯大学西南医学中心等机构的科学家们通过研究在乳腺癌中识别出了一种致病性的信号通路，其或有望为开发治疗这种常见乳腺癌的新型疗法提供潜在的新型靶点。 本文研究基于此前研究结果，此前研究中，研究人员识别出了一种名为ZMYND8的基因或能作为乳腺肿瘤生长的调节子，这项研究中，研究人员进一步分析了乳腺癌发生过程中ZMYND8的关键角色以及27-羟基胆固醇的水平，研究者Weibo Luo说道，本文研究确定了诱发乳腺癌的一种原因，乳腺癌是全球女性因癌症相关死亡的主要原因，这项新的研究发现代表着研究人员向开发新型有效疗法并尽可能早地确定患者的乳腺癌风险又迈出了重要的一步。 乳腺癌的发生始于称之为乳腺癌干细胞的一类细胞群，其具有优越的自我复制能力，这些“坏种子”能驱动肿瘤生长，但其是如何发生的，目前研究人员并不清楚。当识别出了ZMYND8作为乳腺癌生长的调节子后，研究者Luo等人就想通过研究确定是否该基因在肿瘤发生过程中扮演着重要角色。利用对ZMYND8进行敲除的小鼠模型进行研究以及互补的细胞培养实验，研究人员发现，ZMYND8能促进乳腺癌干细胞的维持和自我更新，并能刺激这些细胞转化为肿瘤细胞，从而导致乳腺肿瘤的发生。 识别出一种促进乳腺癌发生的特殊调节子。 图片来源：Science Advances (2022). DOI:10.1126/sciadv.abn5295 研究者指出，ZMYND8的活性会导致27-羟基胆固醇（在人体内胆固醇氧化的主要产物）产量的增加，同时还会阻断27-羟基胆固醇的分解；胆固醇能帮助控制细胞生存和生长，而27-羟基胆固醇此前则被认为能调节雌激素受体从而促进ER阳性乳腺癌的进展，但其在乳腺癌干细胞及肿瘤开启过程中所扮演的角色，研究人员从未调查过。 由此所产生的27-羟基胆固醇的积累则会导致肝脏X受体（LXR，liver X receptor）的激活，从而就会改变基因表达，这种ZMYND8-27-羟基胆固醇-LXR轴会共同促进ER阳性和三阴性乳腺癌干细胞的活性，并推动其生长为乳腺肿瘤。研究者Luo补充道，本文研究揭示了ZMYND8和27-羟基胆固醇或许能作为开发乳腺癌新型疗法的治疗性靶点，以及能帮助预测患者乳腺癌复发和转移风险的可能性生物标志物。综上，本文研究结果表明，ZMYND8或能作为一种特殊的表观遗传促进子，通过代谢重编程作用来驱动乳腺肿瘤的发生。（生物谷Bioon.com） 原始出处： MAOWU LUO,LEI BAO,YAN CHEN, et al. ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells, Science Advances (2022). DOI: 10.1126/sciadv.abn5295

神经干细胞(NSCs)是分化为神经元或神经胶质细胞(星形胶质细胞或少突胶质细胞)的多能前体细胞。干细胞微环境通过神经发生过程时空调控神经干细胞向神经元的分化。 神经干细胞(NSCs)是分化为神经元或神经胶质细胞(星形胶质细胞或少突胶质细胞)的多能前体细胞。干细胞微环境通过神经发生过程时空调控神经干细胞向神经元的分化。有趣的是，这是一个协调的过程，涉及神经元的发展、神经干细胞的更新、神经命运的指定、迁移和成熟。 特定于神经发生的基因受目标增强子和启动子的表观遗传控制，表观遗传格局的突然变化可能导致严重的病理情况。锌指转录因子在调节包括分化在内的各种细胞过程中起着至关重要的作用。染色质阅读器锌指MyND(髓样，神经质和聋人-1)类型包含8(ZMYND8)，一个全反式维甲酸(ATRA)反应基因，先前被证明在促进神经元谱系相关基因的表达中发挥关键作用。 图片来源: https://doi.org/10.1038/s41419-022-05212-x 近日，来自印度萨哈核物理研究所的研究人员在Cell Death and Disease杂志上发表了题为“ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation”的文章，该研究结果阐明了ZMYND8依赖于不同神经元谱系的转录调控的新机制，包括MAPT，以促进神经分化。 在本研究中，研究者报道了ZMYND8通过正向调节典型的MAPT蛋白编码基因亚型促进神经元分化，MAPT蛋白编码基因亚型是神经元轴突发育的关键角色。此外，ZMYND8通过在表观遗传学上沉默MAPT基因内的关键调节区，从而抑制非蛋白质编码的亚型，如MAPT213的表达，从而调节基因-异构体的转换。 ZMYND8的基因缺失导致MAPT213基因增加，这可能抑制与神经元分化程序相关的亲代MAPT蛋白编码转录本的表达。此外，MAPT213的异位表达导致MAPT蛋白编码转录本的抑制。同样，ZMYND8驱动的转录调控也在其他神经元分化促进基因中观察到。 MAPT213与MAPT全长转录的拮抗关系 图片来源: https://doi.org/10.1038/s41419-022-05212-x 总而言之，本研究结果显示了ZMYND8在促进神经元分化方面的双重功能。它与RNA聚合酶II复合体的相互作用在转录上激活了几个神经元基因，包括MAPT。它通过与转录抑制复合体如NuRD或PRC2结合，抑制基因内转录。此外，它还抑制MAPT213的合成，促进参与神经分化的关键神经基因MAPT的转录。 ZMYND8的这种双重转录调控模式在调节神经元分化程序的多个候选基因中得到了验证，可以被认为是一种普遍的机制。抑制基因内转录和促进神经元基因的全长转录事件可能对癌症预防具有更广泛的意义。因此，ZMYND8可用于将神经母细胞瘤细胞编程为分化表型，具有巨大的治疗潜力。（生物谷 Bioon.com） 参考文献 Santanu Adhikary et al. ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation. Cell Death Dis. 2022 Sep 5;13(9):766. doi: 10.1038/s41419-022-05212-x.