Wang Yu, Zheng Shuai, Gao Huabin, Wang Yuting, Chen Yongyu, Han Anjia
Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Cell Signal. 2025 Mar;127:111634. doi: 10.1016/j.cellsig.2025.111634. Epub 2025 Jan 28.
PR/SET domain 16 (PRDM16) is an important transcription factor in the differentiation process of brown adipocytes, which plays an important role in maintaining the special morphological characteristics and cellular function of brown adipocytes. However, the role of PRDM16 in human colorectal cancer (CRC) is currently unknown.
Methylation sequencing, methylation-specific PCR (MSP), multiple bioinformatics analyses, Co-Immunoprecipitation (Co-IP) assay and Immunofluorescence (IF) staining, in vitro and in vivo functional experiments were performed to study the biological role of PRDM16 in CRC progression.
Our study found that methylation level of PRDM16 was associated with CRC and lung metastasis of CRC by DNA methylation sequencing. Furthermore, we identified methylation sites within the promoter region of PRDM16. PRDM16 expression was significantly lower in human CRC tissue samples and dramatically associated with tumor size, T stage, overall survival rates and disease-free survival rates of CRC patients. Down-regulation of PRDM16 significantly promoted proliferation, migration, and invasion of CRC cells by regulating EMT pathway in vitro and in vivo. Decitabine which was a methylate inhibitor increased PRDM16 expression and inhibited CRC progression in vitro and in vivo. Further study showed that PRDM16 interacted with PPAR γ in nucleus and upregulated its expression in CRC. PPAR γ expression was lower in CRC tissues compared with the adjacent colorectal mucosal tissues. PPAR γ suppressed CRC progression including proliferation, colony formation, migration and invasion via EMT pathway, but not affect PRDM16 expression. Decitabine treatment could reverse the biological effects caused by PPAR γ down-regulation in CRC cells.
Our study first shows that DNA methylation-mediated suppresser role of PRDM16 in CRC progression via PPAR γ/EMT pathway.
PR/SET结构域16（PRDM16）是棕色脂肪细胞分化过程中的一种重要转录因子，在维持棕色脂肪细胞的特殊形态特征和细胞功能方面发挥着重要作用。然而，PRDM16在人类结直肠癌（CRC）中的作用目前尚不清楚。
进行甲基化测序、甲基化特异性PCR（MSP）、多种生物信息学分析、免疫共沉淀（Co-IP）测定和免疫荧光（IF）染色，以及体内外功能实验，以研究PRDM16在CRC进展中的生物学作用。
我们的研究通过DNA甲基化测序发现，PRDM16的甲基化水平与CRC及CRC的肺转移相关。此外，我们确定了PRDM16启动子区域内的甲基化位点。PRDM16在人类CRC组织样本中的表达显著降低，并且与CRC患者的肿瘤大小、T分期、总生存率和无病生存率显著相关。在体外和体内，PRDM16的下调通过调节EMT途径显著促进了CRC细胞的增殖、迁移和侵袭。作为甲基化抑制剂的地西他滨在体外和体内增加了PRDM16的表达并抑制了CRC进展。进一步研究表明，PRDM16在细胞核中与PPARγ相互作用并上调其在CRC中的表达。与相邻的结直肠黏膜组织相比，PPARγ在CRC组织中的表达较低。PPARγ通过EMT途径抑制CRC进展，包括增殖、集落形成、迁移和侵袭，但不影响PRDM16的表达。地西他滨治疗可逆转CRC细胞中PPARγ下调所引起的生物学效应。
我们的研究首次表明，DNA甲基化介导的PRDM16通过PPARγ/EMT途径在CRC进展中发挥抑制作用。
