Spag6, or sperm-associated antigen 6, is a core axonemal component. It plays a crucial role in the formation of cilia and sperm flagella, acting as a scaffolding protein in the center of the flagellar axoneme, which is essential for sperm motility [2,5]. It is also associated with multiple signaling pathways, such as ROS/JNK MAPK, PI3K/AKT, and JAK/STAT, influencing various biological processes like cell growth, apoptosis, and immune response [1,3,6].

In acute myeloid leukemia (AML), over-expression of Spag6 promotes cell growth, reduces ROS levels, and decreases the pro-apoptotic effect of daunorubicin through the ROS/JNK MAPK axis in a GSTP1-dependent manner [1]. It also promotes AML progression by interacting with MYO1D, translocating MYO1D to the cell membrane, and upregulating the EGFR family expression [3]. In myelodysplastic syndromes (MDS), Spag6-knockdown enhances decitabine-induced apoptosis and demethylation of PTEN, and triggers autophagic cell death via the AMPK/mTOR/ULK1 signaling pathway [4,7]. In non-syndromic asthenoteratozoospermia with severe MMAF, homozygous Spag6 variants disrupt sperm flagella ultrastructure and reduce Spag6 protein levels in spermatozoa [2]. In lung squamous cell carcinoma, DNMT3b-mediated hypermethylation of the Spag6 promoter downregulates Spag6, activating the JAK/STAT pathway to promote cancer progression [6].

In conclusion, Spag6 is essential for cilia and sperm flagella formation and sperm motility. Its dysregulation is involved in multiple diseases, including AML, MDS, male infertility, and lung cancer. Studies on Spag6, especially through loss-of-function experiments, have provided insights into the disease mechanisms, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Luo, Jie, Ding, Li, Pan, Shirui, Zhang, Jiamin, Liu, Lin. 2024. SPAG6 overexpression decreases the pro-apoptotic effect of daunorubicin in acute myeloid leukemia cells through the ROS/JNK MAPK axis in a GSTP1-dependent manner. In Frontiers in pharmacology, 15, 1390456. doi:10.3389/fphar.2024.1390456. https://pubmed.ncbi.nlm.nih.gov/39508041/

2. Xu, Chuan, Tang, Dongdong, Shao, Zhongmei, He, Xiaojin, Cao, Yunxia. 2022. Homozygous SPAG6 variants can induce nonsyndromic asthenoteratozoospermia with severe MMAF. In Reproductive biology and endocrinology : RB&E, 20, 41. doi:10.1186/s12958-022-00916-3. https://pubmed.ncbi.nlm.nih.gov/35232447/

3. Mu, Jiao, Yuan, Peng, Luo, Jie, Wang, Bao, Liu, Lin. . Upregulated SPAG6 promotes acute myeloid leukemia progression through MYO1D that regulates the EGFR family expression. In Blood advances, 6, 5379-5394. doi:10.1182/bloodadvances.2021006920. https://pubmed.ncbi.nlm.nih.gov/35667090/

4. Luo, Jie, Mu, Jiao, Zhang, Meng, Zhao, Beibei, Liu, Lin. 2021. SPAG6-silencing enhances decitabine-induced apoptosis and demethylation of PTEN in SKM-1 cells and in a xenograft mouse model. In Leukemia & lymphoma, 62, 2242-2252. doi:10.1080/10428194.2021.1913148. https://pubmed.ncbi.nlm.nih.gov/33843428/

5. Bai, Rong, Chen, Dake, Xiong, Hao, Li, Jialian, Li, Fenge. 2023. SPAG6 c.900 T>C affects boar semen quality and blood-testis barrier function by creating a new splice acceptor site. In Animal genetics, 54, 446-456. doi:10.1111/age.13330. https://pubmed.ncbi.nlm.nih.gov/37211688/

6. Wu, Qianbiao, Yan, Yibo, Shi, Shuo, Qi, Quan, Han, Jiahui. 2022. DNMT3b-mediated SPAG6 promoter hypermethylation affects lung squamous cell carcinoma development through the JAK/STAT pathway. In American journal of translational research, 14, 6964-6977. doi:. https://pubmed.ncbi.nlm.nih.gov/36398260/

7. Zhang, Meng, Luo, Jie, Luo, Xiaohua, Liu, Lin. 2020. SPAG6 silencing induces autophagic cell death in SKM-1 cells via the AMPK/mTOR/ULK1 signaling pathway. In Oncology letters, 20, 551-560. doi:10.3892/ol.2020.11607. https://pubmed.ncbi.nlm.nih.gov/32537026/