Cai Man, Wang Liangyu, Sun Miao, Liu Meixi, Liu Yingchun
Department of Dermatology, General Hospital of Northern Theater Command, Shenyang, China.
Department of Neurology, General Hospital of Northern Theater Command, Shenyang, China.
Pigment Cell Melanoma Res. 2025 Jul;38(4):e70034. doi: 10.1111/pcmr.70034.
Protein arginine methyltransferase 6 (PRMT6), a member of the PRMT family capable of self-arginine methylation, is down-regulated in melanoma, but the specific mechanism is still unclear. Our work demonstrated that PRMT6 overexpression significantly inhibited the ability of melanoma cells to proliferate, tumorigenicity, migration, and invasion, whereas PRMT6 knockdown rescued these malignant behaviors of melanoma cells. Mechanistically, we identified aldehyde dehydrogenase 1A1 (ALDH1A1) as a critical downstream target of PRMT6. PRMT6 knockdown up-regulated ALDH1A1 expression, exacerbating melanoma aggressiveness in vitro. Further investigations revealed that PRMT6 modulates ALDH1A1 expression by catalyzing asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a) and antagonizing the enrichment of histone H3 lysine 4 trimethylation (H3K4me3) at the ALDH1A1 promoter. In addition, dual-luciferase experiments showed that the transcription factor KLF4 may bind to the -1800 ~ +45 sequence of PRMT6, thereby negatively regulating PRMT6 expression in melanoma. Our findings underscore the tumor-suppressive role of PRMT6 in melanoma pathogenesis, highlighting its potential as a novel therapeutic target, particularly for metastatic melanoma.
蛋白质精氨酸甲基转移酶6（PRMT6）是PRMT家族中能够进行自身精氨酸甲基化的成员之一，在黑色素瘤中表达下调，但其具体机制仍不清楚。我们的研究表明，PRMT6过表达显著抑制黑色素瘤细胞的增殖、致瘤性、迁移和侵袭能力，而PRMT6基因敲低则挽救了黑色素瘤细胞的这些恶性行为。从机制上来说，我们确定醛脱氢酶1A1（ALDH1A1）是PRMT6的关键下游靶点。PRMT6基因敲低下调了ALDH1A1的表达，在体外加剧了黑色素瘤的侵袭性。进一步研究表明，PRMT6通过催化组蛋白H3第2位精氨酸的不对称二甲基化（H3R2me2a）并拮抗组蛋白H3赖氨酸4三甲基化（H3K4me3）在ALDH1A1启动子区域的富集来调节ALDH1A1的表达。此外，双荧光素酶实验表明，转录因子KLF4可能与PRMT6的-1800 ~ +45序列结合，从而负向调节黑色素瘤中PRMT6的表达。我们的研究结果强调了PRMT6在黑色素瘤发病机制中的肿瘤抑制作用，突出了其作为新型治疗靶点的潜力，特别是对于转移性黑色素瘤。
