Liu Ziyu, Zhang Nan, Xin Benkai, Shi Yueru, Liang Zehua, Wan Youzhong, Hu Xin
China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China; School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China.
Int J Biol Macromol. 2023 Apr 30;235:123792. doi: 10.1016/j.ijbiomac.2023.123792. Epub 2023 Feb 22.
Bone metastasis is a common and incurable complication of breast cancer. Lysine-specific demethylase 1 (LSD1), a histone demethylase, plays an important role in the metastasis of breast cancer. However, the role of LSD1 in bone metastasis of breast cancer is unclear. We hypothesized that exosomes from LSD1 knockdown breast cancer cells promote bone metastasis by remodeling bone microenvironment. To verify this hypothesis, exosomes from LSD1 knockdown Estrogen receptor-positive cancer cell lines, MCF7 and T47D, were isolated, and the effects of these exosomes on osteoblast and osteoclast differentiation were investigated. Interestingly, exosomes from LSD1 knockdown breast cancer cells inhibited osteoblast differentiation and promoted osteoclast differentiation. Mechanistically, miR-6881-3p was decreased in the exosomes from LSD1 knockdown cells, and miR-6881-3p suppressed the expression of pre-B-cell leukemia homeobox 1 (PBX1) and additional sex combs like-2 (ASXL2), two genes with essential functions in osteoblast and osteoclast differentiations respectively. Transfection of miR-6881-3p into LSD1 knockdown cells reversed the effects of the exosomes on osteoblast and osteoclast differentiations. Our study reveals important roles of LSD1 on the regulation of exosomal miRNAs and the formation of favorable bone microenvironment for metastasis.
骨转移是乳腺癌常见且难以治愈的并发症。赖氨酸特异性去甲基化酶1（LSD1）作为一种组蛋白去甲基化酶，在乳腺癌转移中发挥重要作用。然而，LSD1在乳腺癌骨转移中的作用尚不清楚。我们推测，LSD1基因敲低的乳腺癌细胞分泌的外泌体通过重塑骨微环境促进骨转移。为验证这一假设，我们分离了LSD1基因敲低的雌激素受体阳性癌细胞系MCF7和T47D分泌的外泌体，并研究了这些外泌体对成骨细胞和破骨细胞分化的影响。有趣的是，LSD1基因敲低的乳腺癌细胞分泌的外泌体抑制成骨细胞分化并促进破骨细胞分化。机制上，LSD1基因敲低细胞分泌的外泌体中miR-6881-3p减少，而miR-6881-3p可抑制前B细胞白血病同源盒1（PBX1）和额外性梳样蛋白2（ASXL2）的表达，这两个基因分别在成骨细胞和破骨细胞分化中具有重要功能。将miR-6881-3p转染到LSD1基因敲低的细胞中可逆转外泌体对成骨细胞和破骨细胞分化的影响。我们的研究揭示了LSD1在外泌体miRNA调控以及为转移形成有利骨微环境中的重要作用。
