Laboratory of Cell Cycle Regulation, Centre for DNA Fingerprinting and Diagnostics (CDFD), Uppal, Hyderabad 500039, India.
Graduate Studies, Manipal Academy of Higher Education, Manipal 567104, India.
J Cell Sci. 2022 Oct 15;135(20). doi: 10.1242/jcs.260042. Epub 2022 Oct 20.
Attainment of proper cell shape and the regulation of cell migration are essential processes in the development of an organism. The mixed lineage leukemia (MLL or KMT2A) protein, a histone 3 lysine 4 (H3K4) methyltransferase, plays a critical role in cell-fate decisions during skeletal development and haematopoiesis in higher vertebrates. Rho GTPases - RhoA, Rac1 and CDC42 - are small G proteins that regulate various key cellular processes, such as actin cytoskeleton formation, the maintenance of cell shape and cell migration. Here, we report that MLL regulates the homeostasis of these small Rho GTPases. Loss of MLL resulted in an abnormal cell shape and a disrupted actin cytoskeleton, which lead to diminished cell spreading and migration. MLL depletion affected the stability and activity of Rho GTPases in a SET domain-dependent manner, but these Rho GTPases were not direct transcriptional targets of MLL. Instead, MLL regulated the transcript levels of their chaperone protein RhoGDI1 (also known as ARHGDIA). Using MDA-MB-231, a triple-negative breast cancer cell line with high RhoGDI1 expression, we show that MLL depletion or inhibition by small molecules reduces tumour progression in nude mice. Our studies highlight the central regulatory role of MLL in Rho/Rac/CDC42 signalling pathways. This article has an associated First Person interview with the first author of the paper.
细胞形态的正常获得和细胞迁移的调控是生物发育过程中的基本过程。混合谱系白血病（MLL 或 KMT2A）蛋白是一种组蛋白 3 赖氨酸 4（H3K4）甲基转移酶，在高等脊椎动物的骨骼发育和造血过程中，对细胞命运决定起着至关重要的作用。Rho GTPases（RhoA、Rac1 和 CDC42）是小 G 蛋白，调节各种关键细胞过程，如肌动蛋白细胞骨架的形成、细胞形状的维持和细胞迁移。在这里，我们报告 MLL 调节这些小 Rho GTPases 的动态平衡。MLL 的缺失导致细胞形态异常和肌动蛋白细胞骨架紊乱，从而导致细胞扩散和迁移减少。MLL 耗竭以 SET 结构域依赖的方式影响 Rho GTPases 的稳定性和活性，但这些 Rho GTPases不是 MLL 的直接转录靶标。相反，MLL 调节其伴侣蛋白 RhoGDI1（也称为 ARHGDIA）的转录水平。使用 MDA-MB-231，一种具有高 RhoGDI1 表达的三阴性乳腺癌细胞系，我们表明 MLL 耗竭或小分子抑制可减少裸鼠中的肿瘤进展。我们的研究强调了 MLL 在 Rho/Rac/CDC42 信号通路中的核心调节作用。本文有该论文第一作者的相关第一人称采访。
