Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
Biozentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Cell. 2014 Mar 13;156(6):1259-1273. doi: 10.1016/j.cell.2014.01.053.
Members of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in human cancer, but how they suppress tumorigenesis is currently unclear. Here, we use Drosophila neuroblasts to demonstrate that the SWI/SNF component Osa (ARID1) prevents tumorigenesis by ensuring correct lineage progression in stem cell lineages. We show that Osa induces a transcriptional program in the transit-amplifying population that initiates temporal patterning, limits self-renewal, and prevents dedifferentiation. We identify the Prdm protein Hamlet as a key component of this program. Hamlet is directly induced by Osa and regulates the progression of progenitors through distinct transcriptional states to limit the number of transit-amplifying divisions. Our data provide a mechanistic explanation for the widespread tumor suppressor activity of SWI/SNF. Because the Hamlet homologs Evi1 and Prdm16 are frequently mutated in cancer, this mechanism could well be conserved in human stem cell lineages. PAPERCLIP:
SWI/SNF 染色质重塑复合物的成员是人类癌症中最常发生突变的基因之一，但它们如何抑制肿瘤发生目前尚不清楚。在这里，我们使用果蝇神经母细胞证明，SWI/SNF 成分 Osa（ARID1）通过确保干细胞谱系中的正确谱系进展来预防肿瘤发生。我们表明，Osa 在过渡扩增群体中诱导一个转录程序，该程序启动时间模式，限制自我更新，并防止去分化。我们确定 Prdm 蛋白 Hamlet 是该程序的关键组成部分。Hamlet 被 Osa 直接诱导，并通过不同的转录状态调节祖细胞的进展，以限制过渡扩增分裂的数量。我们的数据为 SWI/SNF 的广泛肿瘤抑制活性提供了一种机制解释。由于 Hamlet 同源物 Evi1 和 Prdm16 在癌症中经常发生突变，因此该机制很可能在人类干细胞谱系中保守。
