DNAJC12, a co-chaperone protein, is involved in multiple biological processes. It is responsible for the proper folding of phenylalanine hydroxylase (PAH) along with 70kDa heat shock protein (HSP70), thus playing a role in monoamine synthesis [2,3]. It has also been implicated in various signaling pathways such as the PI3K-AKT pathway, β-catenin signaling pathway, and may be part of a regulatory network with ESR1 and ERBB4 in breast carcinoma cells [1,5,8].

In breast cancer, DNAJC12 expression is linked to chemotherapy resistance. High DNAJC12 expression is associated with a lower pathological complete response rate. It inhibits doxorubicin-induced ferroptosis and apoptosis through activation of AKT in an HSP70-dependent manner [1]. In rectal and lung cancers, DNAJC12 promotes tumorigenesis. In rectal cancer, it facilitates cell proliferation and migration and inhibits apoptosis via the DNAJC12/HSPA4 axis [7]. In lung cancer, it promotes cell proliferation, migration, and invasion by regulating the activation of β-catenin [8]. In neuroblastoma, down-regulation of DNAJC12 is associated with poor prognosis as it activates glycolysis, increases histone H4K5 lactylation, and up-regulates COL1A1 involved in cell metastasis [4]. Also, DNAJC12 deficiency is related to hyperphenylalaninemia, neurodevelopmental delay, dystonia, parkinsonism, and can present with restless legs syndrome [2,3,6,9,10].

In summary, DNAJC12 is a crucial co-chaperone with diverse functions in normal biological processes and disease conditions. Its role in cancer, especially in promoting tumorigenesis and chemotherapy resistance, as well as in neurological and metabolic disorders, highlights its significance. Studies using various models help in understanding its functions and may provide potential therapeutic targets for these diseases.

References:

1. Shen, Mengjia, Cao, Shiyu, Long, Xinyi, Ye, Feng, Bu, Hong. 2024. DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT. In Redox biology, 70, 103035. doi:10.1016/j.redox.2024.103035. https://pubmed.ncbi.nlm.nih.gov/38306757/

2. Deng, Isaac Bul, Follett, Jordan, Bu, Mengfei, Farrer, Matthew J. 2023. DNAJC12 in Monoamine Metabolism, Neurodevelopment, and Neurodegeneration. In Movement disorders : official journal of the Movement Disorder Society, 39, 249-258. doi:10.1002/mds.29677. https://pubmed.ncbi.nlm.nih.gov/38014588/

3. Blau, Nenad, Martinez, Aurora, Hoffmann, Georg F, Thöny, Beat. 2017. DNAJC12 deficiency: A new strategy in the diagnosis of hyperphenylalaninemias. In Molecular genetics and metabolism, 123, 1-5. doi:10.1016/j.ymgme.2017.11.005. https://pubmed.ncbi.nlm.nih.gov/29174366/

4. Yang, Yaqi, Wen, Jiejun, Lou, Susu, Ma, Jing, Shen, Nan. 2024. DNAJC12 downregulation induces neuroblastoma progression via increased histone H4K5 lactylation. In Journal of molecular cell biology, , . doi:10.1093/jmcb/mjae056. https://pubmed.ncbi.nlm.nih.gov/39716470/

5. Lin, Mianjie, Wang, Ya-Nan, Ye, Yixin, Guo, Fengbiao, Chen, Haibin. 2021. DNAJC12 as a Mediator Between ESR1 and ERBB4 in Breast Carcinoma Cells. In Frontiers in oncology, 11, 582277. doi:10.3389/fonc.2021.582277. https://pubmed.ncbi.nlm.nih.gov/33718139/

6. Porta, Francesco, Neirotti, Alessandro, Spada, Marco. 2023. Restless legs syndrome in DNAJC12 deficiency. In Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 44, 2167-2172. doi:10.1007/s10072-023-06733-9. https://pubmed.ncbi.nlm.nih.gov/36897462/

7. Sun, Qi, Lv, Yan, Sun, Weihua. 2022. Inhibition of DNAJC12 Inhibited Tumorigenesis of Rectal Cancer via Downregulating HSPA4 Expression. In Evidence-based complementary and alternative medicine : eCAM, 2022, 1027895. doi:10.1155/2022/1027895. https://pubmed.ncbi.nlm.nih.gov/36185081/

8. Li, Yun, Li, Meng, Jin, Fengqi, Chen, Minghui, Yin, Jingjing. 2021. DNAJC12 promotes lung cancer growth by regulating the activation of β‑catenin. In International journal of molecular medicine, 47, . doi:10.3892/ijmm.2021.4938. https://pubmed.ncbi.nlm.nih.gov/33907820/

9. Fino, Edoardo, Barbato, Alessandro, Scaturro, Giusi M, Procopio, Elena, Balestrini, Simona. 2023. DNAJC12 deficiency: Mild hyperphenylalaninemia and neurological impairment in two siblings. In Molecular genetics and metabolism reports, 37, 101008. doi:10.1016/j.ymgmr.2023.101008. https://pubmed.ncbi.nlm.nih.gov/38053929/

10. Straniero, Letizia, Guella, Ilaria, Cilia, Roberto, Rajput, Ali H, Duga, Stefano. 2017. DNAJC12 and dopa-responsive nonprogressive parkinsonism. In Annals of neurology, 82, 640-646. doi:10.1002/ana.25048. https://pubmed.ncbi.nlm.nih.gov/28892570/