Cbx3, also known as chromobox protein homolog 3 or HP1γ, is a member of the heterochromatin-associated protein 1 (HP1) family. It plays crucial roles in epigenetic regulation, such as through histone modifications, and is involved in multiple key pathways including PI3K/AKT, Ras/KRAS, Wnt/β-catenin, MAPK, Notch, and p53 [4]. It is of great biological importance as it impacts processes like cell cycle regulation, immune evasion, and cancer progression. Genetic models, especially gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying Cbx3.

In glioblastoma, lactate-induced histone lactylation leads to immunosuppressive transcriptional programs via Cbx3, and targeting Cbx3 inhibits tumor growth [1]. In prostate cancer, CBX3 is upregulated in CDK4/6 inhibitors-resistant cells, and a dual BET/PLK1 inhibitor can increase the sensitivity of CRPC cells to CDK4/6 inhibitors partially through CBX3 [2]. In colon, CBX3 deletion results in chronic inflammation due to its antagonism of the IFNγ/STAT1/PD-L1 axis, and also heightens CRC cells' chemosensitivity [3]. In colorectal carcinoma, CBX3 promotes multidrug resistance by suppressing ferroptosis via the CUL3/NRF2/GPX2 axis [5].

In conclusion, Cbx3 is a significant epigenetic regulator involved in diverse biological processes. KO/CKO mouse models have revealed its roles in cancer-related immune evasion, drug resistance, and inflammation. Understanding Cbx3's functions can provide potential therapeutic targets for various cancers, including glioblastoma, prostate cancer, CRC, and others.

References:

1. Wang, Shuai, Huang, Tengfei, Wu, Qiulian, Placantonakis, Dimitris G, Rich, Jeremy N. 2024. Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation. In The Journal of clinical investigation, 134, . doi:10.1172/JCI176851. https://pubmed.ncbi.nlm.nih.gov/39545414/

2. Liang, Huaiyuan, Yang, Chunguang, Zeng, Ruijiang, Yan, Binyuan, Jin, Xin. 2023. Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2302368. doi:10.1002/advs.202302368. https://pubmed.ncbi.nlm.nih.gov/37949681/

3. Xiang, Yao, Mata-Garrido, Jorge, Fu, Yuanji, Arbibe, Laurence, Chang, Yunhua. 2024. CBX3 antagonizes IFNγ/STAT1/PD-L1 axis to modulate colon inflammation and CRC chemosensitivity. In EMBO molecular medicine, 16, 1404-1426. doi:10.1038/s44321-024-00066-6. https://pubmed.ncbi.nlm.nih.gov/38684864/

4. Wahab, Muhammad Aamir, Del Gaudio, Nunzio, Gargiulo, Biagio, Altucci, Lucia, Conte, Mariarosaria. 2024. Exploring the Role of CBX3 as a Potential Therapeutic Target in Lung Cancer. In Cancers, 16, . doi:10.3390/cancers16173026. https://pubmed.ncbi.nlm.nih.gov/39272883/

5. Bai, Xiaoming, Duan, Tinghong, Shao, Jiaofang, Zhou, Jin-Yong, Pan, Jinshun. 2025. CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis. In Oncogene, , . doi:10.1038/s41388-025-03337-9. https://pubmed.ncbi.nlm.nih.gov/40089640/