DIAPH3, a member of the formin proteins, has the capacity to nucleate and elongate actin filaments, remodeling the cytoskeleton. It is involved in multiple biological processes such as cytokinesis, mitotic spindle regulation, and actin cytoskeleton remodeling. Signaling pathways related to DIAPH3 include ERK signaling, and it is of great biological importance in processes like cell division, migration, and neurogenesis [2,4,5]. Genetic models, especially knockout models, are valuable for studying DIAPH3's functions.

In hepatocellular carcinoma, LINC01089-a super enhancer-driven lncRNA, interacts with hnRNPM to induce skipping of DIAPH3 exon 3, reducing DIAPH3 protein levels, which in turn activates the ERK/Elk1/Snail axis and promotes epithelial-mesenchymal transition and metastasis [1]. In lung adenocarcinoma, DIAPH3 is up-regulated and promotes tumor cell growth by interacting with STK38, impairing the STK38-MEKK interaction and activating ERK signaling [3]. Conditional inactivation of Diaph3 in mouse cerebral cortex disrupts neurogenesis, leading to cortical malformation and autistic-like behavior, as DIAPH3 deficiency causes disorganized cytoskeleton, multipolar spindles, and affects the expression/stability of proteins like SPAG5 [4]. In pancreatic cancer, DIAPH3 is highly expressed and promotes cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects [6]. In colorectal cancer, DIAPH3 is down-regulated, and its knockdown promotes cell proliferation and migration by inhibiting EGFR degradation [7].

In conclusion, DIAPH3 plays essential roles in multiple biological processes, mainly through its function in cytoskeleton remodeling. KO/CKO mouse models have been crucial in revealing its role in diseases such as liver, lung, pancreatic, colorectal cancers, and brain-related disorders, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Su, Tao, Zhang, Nasha, Wang, Teng, Han, Linyu, Yang, Ming. . Super Enhancer-Regulated LncRNA LINC01089 Induces Alternative Splicing of DIAPH3 to Drive Hepatocellular Carcinoma Metastasis. In Cancer research, 83, 4080-4094. doi:10.1158/0008-5472.CAN-23-0544. https://pubmed.ncbi.nlm.nih.gov/37756562/

2. Zhang, Ke, Huang, Miaodan, Li, Ang, Qin, Dajiang, Su, Huanxing. 2023. DIAPH3 condensates formed by liquid-liquid phase separation act as a regulatory hub for stress-induced actin cytoskeleton remodeling. In Cell reports, 42, 111986. doi:10.1016/j.celrep.2022.111986. https://pubmed.ncbi.nlm.nih.gov/36640348/

3. Xiang, Guo, Weiwei, He, Erji, Gao, Haitao, Ma. 2019. DIAPH3 promotes the tumorigenesis of lung adenocarcinoma. In Experimental cell research, 385, 111662. doi:10.1016/j.yexcr.2019.111662. https://pubmed.ncbi.nlm.nih.gov/31586548/

4. Lau, Eva On-Chai, Damiani, Devid, Chehade, Georges, Gailly, Philippe, Tissir, Fadel. 2021. DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction. In eLife, 10, . doi:10.7554/eLife.61974. https://pubmed.ncbi.nlm.nih.gov/33899739/

5. Shah, Riya, Panagiotou, Thomas C, Cole, Gregory B, McCulloch, Christopher A, Wilde, Andrew. 2024. The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow. In Nature communications, 15, 5250. doi:10.1038/s41467-024-49427-2. https://pubmed.ncbi.nlm.nih.gov/38897998/

6. Rong, Yefei, Gao, Jie, Kuang, Tiantao, Li, Zhi, Lou, Wenhui. 2020. DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects. In Journal of cellular and molecular medicine, 25, 2163-2175. doi:10.1111/jcmm.16196. https://pubmed.ncbi.nlm.nih.gov/33345387/

7. Huang, Renli, Wu, Cheng, Wen, Jialing, Yu, Jinlong, Zou, Zhaowei. 2022. DIAPH3 is a prognostic biomarker and inhibit colorectal cancer progression through maintaining EGFR degradation. In Cancer medicine, 11, 4688-4702. doi:10.1002/cam4.4793. https://pubmed.ncbi.nlm.nih.gov/35538918/