LSD1 的 R251Q 突变促进腔型乳腺癌细胞的侵袭和迁移。

The R251Q mutation of LSD1 promotes invasion and migration of luminal breast cancer cells.

机构信息

China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China; School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.

School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.

出版信息

Int J Biol Macromol. 2020 Dec 1;164:4000-4009. doi: 10.1016/j.ijbiomac.2020.08.221. Epub 2020 Aug 31.

DOI:10.1016/j.ijbiomac.2020.08.221

PMID:32882276

Abstract

LSD1 (KDM1A), a histone demethylase, plays important roles in breast cancer. The breast cancer patients with LSD1 mutation show significantly worse outcomes compared to those without LSD1 mutation. The R251Q mutation of LSD1 increases the invasion and migration of luminal breast cancer cells. Furthermore, the R251Q mutation of LSD1 alters the expression of genes that modulates the epithelial to mesenchymal transition. Additionally, the R251Q mutation impairs the H3K4me2 demethylation activity of LSD1 by abolishing the interaction between LSD1 and CoREST, which leads to the increased expression of TRIM37, a histone H2A ubiquitin ligase that regulates the expression of E-cadherin. Collectively, our results suggest that the R251Q mutation abolishes the tumor suppressive effects of LSD1 on luminal breast cancer cells by disrupting the formation of functional LSD1/CoREST/HDAC complexes.

摘要

LSD1（KDM1A）是一种组蛋白去甲基化酶，在乳腺癌中发挥着重要作用。与 LSD1 无突变的乳腺癌患者相比，LSD1 突变的乳腺癌患者预后明显较差。LSD1 的 R251Q 突变增加了腔型乳腺癌细胞的侵袭和迁移。此外，LSD1 的 R251Q 突变改变了调节上皮间质转化的基因表达。此外，R251Q 突变通过消除 LSD1 与 CoREST 之间的相互作用，破坏 LSD1 的 H3K4me2 去甲基化活性，导致组蛋白 H2A 泛素连接酶 TRIM37 的表达增加，从而调节 E-钙粘蛋白的表达。综上所述，我们的研究结果表明，R251Q 突变通过破坏功能性 LSD1/CoREST/HDAC 复合物的形成，消除 LSD1 对腔型乳腺癌细胞的肿瘤抑制作用。