Brd8-KO Mouse

Brd8, also known as skeletal muscle abundant protein and thyroid hormone receptor coactivating protein of 120 kDa (TrCP120), is a subunit of the NuA4/TIP60-histone acetyltransferase complex. It functions in transcriptional modulation by recognizing acetylated lysine residues on histones and other proteins, recruiting various transcription factors and protein complexes. Brd8 is involved in cell proliferation, response to cytotoxic agents, and maintaining cell-type stability during embryonic development [2,7].

In glioblastoma (GBM), Brd8 maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex, causing a repressive chromatin state that prevents p53-mediated transactivation and sustains proliferation. Targeting its bromodomain can displace H2AZ, enhance chromatin accessibility, and enforce cell cycle arrest and tumour suppression in TP53 wild-type GBM [1]. In hepatocellular carcinoma (HCC), Brd8 promotes cell proliferation and apoptosis resistance, and is negatively regulated by miR-876-3p [3]. In colorectal cancer cells, depletion of Brd8 induces cell-cycle arrest at the G1 phase and suppresses cell proliferation [4]. In human lung epithelial cells, depletion of Brd8 increases the secretion of antimicrobial peptides and chemokines, and reduces cell proliferation [5]. In cancer metastasis, knockdown of Brd8 abolishes the interaction between TWIST1 and the TIP60-Com complex, decreasing TWIST1-activated target gene expression and cancer metastasis [6]. In aggressive/metastatic colorectal cancers, siRNA-mediated knockdown of Brd8 induces cell death or growth delay, and surviving cells are sensitive to spindle poisons and a proteasome inhibitor [8].

In summary, Brd8 plays crucial roles in multiple biological processes, especially in cancer-related cell proliferation, apoptosis, and metastasis. Loss-of-function experiments in different cell models, such as those in GBM, HCC, and colorectal cancer, have revealed its potential as a therapeutic target for these diseases.

References:

1. Sun, Xueqin, Klingbeil, Olaf, Lu, Bin, Vakoc, Christopher R, Mills, Alea A. 2022. BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network. In Nature, 613, 195-202. doi:10.1038/s41586-022-05551-x. https://pubmed.ncbi.nlm.nih.gov/36544023/

2. Yamaguchi, Kiyoshi, Nakagawa, Saya, Furukawa, Yoichi. 2024. Understanding the role of BRD8 in human carcinogenesis. In Cancer science, 115, 2862-2870. doi:10.1111/cas.16263. https://pubmed.ncbi.nlm.nih.gov/38965933/

3. Yu, Zhaoxiang, Chen, Tianxiang, Mo, Huanye, Guo, Cheng, Liu, Qingguang. 2020. BRD8, which is negatively regulated by miR-876-3p, promotes the proliferation and apoptosis resistance of hepatocellular carcinoma cells via KAT5. In Archives of biochemistry and biophysics, 693, 108550. doi:10.1016/j.abb.2020.108550. https://pubmed.ncbi.nlm.nih.gov/32860757/

4. Yamaguchi, Kiyoshi, Nakagawa, Saya, Saku, Akari, Imoto, Seiya, Furukawa, Yoichi. 2023. Bromodomain protein BRD8 regulates cell cycle progression in colorectal cancer cells through a TIP60-independent regulation of the pre-RC complex. In iScience, 26, 106563. doi:10.1016/j.isci.2023.106563. https://pubmed.ncbi.nlm.nih.gov/37123243/

5. Browne, James A, NandyMazumdar, Monali, Paranjapye, Alekh, Leir, Shih-Hsing, Harris, Ann. 2021. The Bromodomain Containing 8 (BRD8) transcriptional network in human lung epithelial cells. In Molecular and cellular endocrinology, 524, 111169. doi:10.1016/j.mce.2021.111169. https://pubmed.ncbi.nlm.nih.gov/33476703/

6. Yu, Xiaobin, He, Tao, Tong, Zhangwei, Edwards, Dean P, Xu, Jianming. 2023. Molecular mechanisms of TWIST1-regulated transcription in EMT and cancer metastasis. In EMBO reports, 24, e56902. doi:10.15252/embr.202356902. https://pubmed.ncbi.nlm.nih.gov/37680145/

7. Sun, Li, Fu, Xiuling, Xiao, Zhen, Jauch, Ralf, Hutchins, Andrew Paul. 2024. BRD8 Guards the Pluripotent State by Sensing and Maintaining Histone Acetylation. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12, e2409160. doi:10.1002/advs.202409160. https://pubmed.ncbi.nlm.nih.gov/39656858/

8. Yamada, Hiroshi Y, Rao, Chinthalapally V. . BRD8 is a potential chemosensitizing target for spindle poisons in colorectal cancer therapy. In International journal of oncology, 35, 1101-9. doi:. https://pubmed.ncbi.nlm.nih.gov/19787264/