Ding Yu, Herman Jacob A, Toledo Chad M, Lang Jackie M, Corrin Philip, Girard Emily J, Basom Ryan, Delrow Jeffrey J, Olson James M, Paddison Patrick J
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Novartis Institute for Biomedical Research, Shanghai, China.
Oncotarget. 2017 Jul 25;8(30):48545-48562. doi: 10.18632/oncotarget.18153.
Zinc finger domain genes comprise ~3% of the human genome, yet many of their functions remain unknown. Here we investigated roles for the vertebrate-specific BTB domain zinc finger gene ZNF131 in the context of human brain tumors. We report that ZNF131 is broadly required for Glioblastoma stem-like cell (GSC) viability, but dispensable for neural progenitor cell (NPC) viability. Examination of gene expression changes after ZNF131 knockdown (kd) revealed that ZNF131 activity notably promotes expression of Joubert Syndrome ciliopathy genes, including KIF7, NPHP1, and TMEM237, as well as HAUS5, a component of Augmin/HAUS complex that facilitates microtubule nucleation along the mitotic spindle. Of these genes only kd of HAUS5 displayed GSC-specific viability loss. Critically, HAUS5 ectopic expression was sufficient to suppress viability defects of ZNF131 kd cells. Moreover, ZNF131 and HAUS5 kd phenocopied each other in GSCs, each causing: mitotic arrest, centrosome fragmentation, loss of Augmin/HAUS complex on the mitotic spindle, and loss of GSC self-renewal and tumor formation capacity. In control NPCs, we observed centrosome fragmentation and lethality only when HAUS5 kd was combined with kd of HAUS2 or HAUS4, demonstrating that the complex is essential in NPCs, but that GSCs have heightened requirement. Our results suggest that GSCs differentially rely on ZNF131-dependent expression of HAUS5 as well as the Augmin/HAUS complex activity to maintain the integrity of centrosome function and viability.
锌指结构域基因约占人类基因组的3%，但其许多功能仍不为人知。在此，我们研究了脊椎动物特有的BTB结构域锌指基因ZNF131在人类脑肿瘤中的作用。我们报告称，胶质母细胞瘤干细胞样细胞（GSC）的存活广泛需要ZNF131，但神经祖细胞（NPC）的存活则不需要它。对ZNF131敲低（kd）后基因表达变化的检测显示，ZNF131的活性显著促进了Joubert综合征纤毛病基因的表达，包括KIF7、NPHP1和TMEM237，以及HAUS5，后者是促进有丝分裂纺锤体微管成核的Augmin/HAUS复合体的一个组成部分。在这些基因中，只有HAUS5的kd表现出GSC特异性的存活丧失。至关重要的是，HAUS5的异位表达足以抑制ZNF131 kd细胞的存活缺陷。此外，ZNF131和HAUS5的kd在GSCs中表现出相互模拟的现象，各自导致：有丝分裂停滞、中心体碎片化、有丝分裂纺锤体上Augmin/HAUS复合体的丧失，以及GSC自我更新和肿瘤形成能力的丧失。在对照NPCs中，我们仅在HAUS5的kd与HAUS2或HAUS4的kd联合时观察到中心体碎片化和致死性，这表明该复合体在NPCs中是必不可少的，但GSCs对其有更高的需求。我们的结果表明，GSCs不同程度地依赖ZNF131依赖的HAUS5表达以及Augmin/HAUS复合体活性来维持中心体功能和存活的完整性。
