Jeong Su-Jin, Oh Ji Hoon, Cho Je-Yoel
Department of Biochemistry, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea.
Comparative Medicine Disease Research Center, Seoul National University, Seoul, 08826, Republic of Korea.
Heliyon. 2024 Sep 16;10(19):e37749. doi: 10.1016/j.heliyon.2024.e37749. eCollection 2024 Oct 15.
Breast cancer is one of the most common malignant tumors in women worldwide. Similarly, Canine mammary tumors (CMTs) are mostly diagnosed as spontaneous diseases in female dogs. Many studies have suggested that CMTs serve as good models for human breast cancer. However, comparative approaches to histone modifications are still lacking. This study aimed to compare the canine mammary tumor Histone H3 lysine 4 trimethylation (H3K4me3) landscape with that in human breast cancer. Our H3K4me3 ChIP-seq data from CMTs revealed a significant enrichment of H3K4me3 in the ALYREF gene promoter in tumor tissues compared to normal tissues. Furthermore, our study and publicly available RNA-sequencing data revealed that expression was elevated in malignant tissues and breast cancer cell lines, and its upregulation was associated with poor prognosis in humans. Depletion of ALYREF resulted in changes in cellular phenotypes, including increased proliferation and colony formation, as well as decreased apoptosis increased cell viability and anchorage-independent growth while decreasing apoptosis by regulating the mRNA expression and protein levels of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), which promotes hormone receptor-positive breast cancer and CMTs via epigenetic modifications. This suggests that may function as a contributing factor to malignant transformation in both CMT and human breast cancer.
乳腺癌是全球女性中最常见的恶性肿瘤之一。同样，犬乳腺肿瘤（CMTs）大多被诊断为雌性犬的自发性疾病。许多研究表明，CMTs可作为人类乳腺癌的良好模型。然而，目前仍缺乏对组蛋白修饰的比较研究方法。本研究旨在比较犬乳腺肿瘤中组蛋白H3赖氨酸4三甲基化（H3K4me3）图谱与人类乳腺癌中的图谱。我们来自CMTs的H3K4me3 ChIP-seq数据显示，与正常组织相比，肿瘤组织中ALYREF基因启动子区域的H3K4me3显著富集。此外，我们的研究以及公开可用的RNA测序数据表明，其在恶性组织和乳腺癌细胞系中的表达升高，并且其上调与人类的不良预后相关。敲低ALYREF会导致细胞表型发生变化，包括增殖增加、集落形成增加以及凋亡减少，同时通过调节增强子zeste 2多梳抑制复合物2亚基（EZH2）的mRNA表达和蛋白水平来增加细胞活力和非锚定依赖性生长，而EZH2通过表观遗传修饰促进激素受体阳性乳腺癌和CMTs。这表明ALYREF可能是CMT和人类乳腺癌恶性转化的一个促成因素。
