Abstract
Breast cancer is the most prevalent cancer in women worldwide, which remains incurable once metastatic. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells which are essential in tumor formation, metastasis, and drug resistance. microRNAs (miRNAs) play important roles in the breast cancer cells and BCSCs by regulating specific genes. In this study, we found that miR-29a was up-regulated in BCSCs, in aggressive breast cancer cell line and in breast cancer tissues. We also confirmed suppressor of variegation 4–20 homolog 2 (SUV420H2), which is a histone methyltransferase that specifically trimethylates Lys-20 of histone H4 (H4K20), as the target of miR-29a. Both miR-29a overexpression and SUV420H2 knockdown in breast cancer cells promoted their migration and invasion in vitro and in vivo. Furthermore, we discovered that SUV420H2-targeting miR-29a attenuated the repression of connective tissue growth factor (CTGF) and growth response protein-1 (EGR1) by H4K20 trimethylation and promoted the EMT progress of breast cancer cells. Taken together, our findings reveal that miR-29a plays critical roles in the EMT and metastasis of breast cancer cells through targeting SUV420H2. These findings may provide new insights into novel molecular therapeutic targets for breast cancer.
Highlights
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide
Results miR-29a is up-regulated in breast cancer due to basic fibroblast growth factor (bFGF) miR-29a was reported up-regulated in MCF-7 spheroid cells, and CD44+/CD24− MCF-7 cell compared with
We compared the expression levels of miR-29a in 12 pairs of human breast cancer tissues and their corresponding distal noncancerous tissues, and in a more aggressive breast cancer cell line, MDA-MB-231 cells, which contains high ratio of CD44+/CD24− cells (~80%). miR-29a levels were remarkably higher in breast cancer tissues compared with those noncancerous counterparts (Fig. 1d), as well as in MDA-MB-231 cells compared to MCF-7 cells (Fig. 1e)
Summary
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide. The importance of many other differentially expressed miRNAs and their roles in regulating breast cancer cells or BCSCs properties remains to be determined. Epigenetic alterations such as DNA methylation and histone modifications occur in many cancers[7,8,9]. Aberrant histone modifications are associated with carcinogenesis and cancer progression by affecting genomic integrity and by altering the expressions of related genes. The decrease in H4K20me[3] in cancer cells is found associated with diminished expression of SUV420H2, which is a histone lysine methyltransferase that trimethylates histone H4K20. It has been shown that ectopic expression of SUV420H2, which caused the increase of H4K20me[3], suppressed MDA-MB231 cells invasion by targeting tensin-315
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