PRMT6, or protein arginine methyltransferase 6, is a type I PRMT. It is involved in epigenetic regulation of gene expression by methylating histone and non-histone proteins. This methylation influences various processes such as alternative splicing, DNA repair, cell proliferation, senescence, and cell signaling [7].

In multiple diseases, PRMT6 has shown distinct roles. In breast cancer, it positively regulates metastasis through methylating STAT3 at arginine 729, which is crucial for STAT3's membrane localization, interaction with JAK2, phosphorylation at Y705, and cancer cell metastasis. The PRMT6 inhibitor EPZ020411 can curtail breast cancer metastasis [1]. In glioblastoma, PRMT6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells. Disrupting the CK2-PRMT6-RCC1 signaling axis affects mitosis, and the inhibitor EPZ020411 improves radiotherapy cytotoxicity [2]. In lung cancer, PRMT6 is highly expressed and regulates cell metabolism, tumorigenicity, and cisplatin response by enhancing the activity of 6PGD and ENO1 [3]. In acute myeloid leukemia, PRMT6 is key for maintaining leukemia stem cells. Genetic deletion or inhibition of PRMT6 impairs AML development [4]. In neuropathic pain, PRMT6 deficiency or inhibition alleviates pain by decreasing glycolysis and inflammation in microglia [5]. In diabetic nephropathy, downregulation of PRMT6 participates in kidney dysfunction and renal cell death via ferroptosis, and the PRMT6/STAT1/ACSL1 axis may be a new therapeutic target [6]. In glioblastoma, silencing PRMT6 inhibits cell proliferation and induces cell cycle arrest, as PRMT6 promotes the degradation of CDKN1B via CDC20, and the inhibitor EPZ020411 can attenuate GBM cell proliferation [8]. Also in glioblastoma, PRMT6-mediated transcriptional activation of YTHDF2 promotes migration, invasion, and EMT via the Wnt-β-catenin pathway [10]. In osteoporosis, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss by reversing the metabolic shift from fatty acid oxidation to glycolysis [9].

In conclusion, PRMT6 is a crucial regulator in multiple biological processes and diseases. Gene knockout or inhibition studies in mouse models for PRMT6 have revealed its roles in cancer metastasis, cell proliferation, stem-cell maintenance, pain, and metabolic regulation, providing potential therapeutic targets for breast cancer, glioblastoma, lung cancer, AML, neuropathic pain, diabetic nephropathy, and osteoporosis.

References:

1. Chen, Qianzhi, Hu, Qingyi, Chen, Yan, Li, Lei, Li, Junjun. 2023. PRMT6 methylation of STAT3 regulates tumor metastasis in breast cancer. In Cell death & disease, 14, 655. doi:10.1038/s41419-023-06148-6. https://pubmed.ncbi.nlm.nih.gov/37813837/

2. Huang, Tianzhi, Yang, Yongyong, Song, Xiao, Hu, Bo, Cheng, Shi-Yuan. 2021. PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells. In Molecular cell, 81, 1276-1291.e9. doi:10.1016/j.molcel.2021.01.015. https://pubmed.ncbi.nlm.nih.gov/33539787/

3. Sun, Mingming, Li, Leilei, Niu, Yujia, Zhang, Shuai, Shan, Changliang. 2022. PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism. In Acta pharmaceutica Sinica. B, 13, 157-173. doi:10.1016/j.apsb.2022.05.019. https://pubmed.ncbi.nlm.nih.gov/36815049/

4. Cheng, Ying, Gao, Zhuying, Zhang, Tiantian, Zhou, Fuling, Zhang, Haojian. 2022. Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance. In Cell stem cell, 30, 69-85.e7. doi:10.1016/j.stem.2022.12.003. https://pubmed.ncbi.nlm.nih.gov/36574771/

5. Hua, Tong, Kong, Erliang, Zhang, Hailing, Han, Chaofeng, Yuan, Hongbin. 2024. PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia. In Brain, behavior, and immunity, 118, 101-114. doi:10.1016/j.bbi.2024.02.027. https://pubmed.ncbi.nlm.nih.gov/38402915/

6. Hong, Jia, Li, Xue, Hao, Yingxiang, Zhang, Jianhai, Zhu, Minmin. 2024. The PRMT6/STAT1/ACSL1 axis promotes ferroptosis in diabetic nephropathy. In Cell death and differentiation, 31, 1561-1575. doi:10.1038/s41418-024-01357-8. https://pubmed.ncbi.nlm.nih.gov/39134684/

7. Chen, Zhixian, Gan, Jianfeng, Wei, Zhi, Xu, Congjian, Zhao, Hongbo. 2022. The Emerging Role of PRMT6 in Cancer. In Frontiers in oncology, 12, 841381. doi:10.3389/fonc.2022.841381. https://pubmed.ncbi.nlm.nih.gov/35311114/

8. Wang, Ji, Xiao, Zongyu, Li, Peng, Lan, Qing, Wang, Yezhong. 2023. PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B. In Oncogene, 42, 1088-1100. doi:10.1038/s41388-023-02624-7. https://pubmed.ncbi.nlm.nih.gov/36792756/

9. Chu, Wenxiang, Peng, Weilin, Lu, Yingying, Han, Chaofeng, Lu, Xuhua. 2024. PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2403177. doi:10.1002/advs.202403177. https://pubmed.ncbi.nlm.nih.gov/39120025/

10. Yu, Peng, Xu, Tutu, Ma, Wenmeng, Sun, Yongqing, Li, Guangyu. 2024. PRMT6-mediated transcriptional activation of ythdf2 promotes glioblastoma migration, invasion, and emt via the wnt-β-catenin pathway. In Journal of experimental & clinical cancer research : CR, 43, 116. doi:10.1186/s13046-024-03038-3. https://pubmed.ncbi.nlm.nih.gov/38637831/