Abstract
Epigenetic abnormalities affect tumor progression, as well as gene expression and function. Among the diverse epigenetic modulators, the histone methyltransferase G9a has been focused on due to its role in accelerating tumorigenesis and metastasis. Although epigenetic dysregulation is closely related to tumor progression, reports regarding the relationship between G9a and its possible downstream factors regulating breast tumor growth are scarce. Therefore, we aimed to verify the role of G9a and its presumable downstream regulators during malignant progression of breast cancer. G9a-depleted MCF7 and T47D breast cancer cells exhibited suppressed motility, including migration and invasion, and an improved response to ionizing radiation. To identify the possible key factors underlying these effects, microarray analysis was performed, and a TGF-β superfamily member, BMP5, was selected as a prominent target gene. It was found that BMP5 expression was markedly increased by G9a knockdown. Moreover, reduction in the migration/invasion ability of MCF7 and T47D breast cancer cells was induced by BMP5. Interestingly, a G9a-depletion-mediated increase in BMP5 expression induced the phosphorylation of Smad proteins, which are the intracellular signaling mediators of BMP5. Accordingly, we concluded that the observed antitumor effects may be based on the G9a-depletion-mediated increase in BMP5 expression and the consequent facilitation of Smad protein phosphorylation.
Highlights
Breast cancer is a malignant tumor that develops around breast tissue and has a high incidence and mortality among women [1]
We suggested that BMP5 is a novel target of G9a, which is responsible for modulating the growth and metastasis of breast cancer cells
To confirm the expression pattern of G9a according to the type of breast cancer, we assessed the level of G9a expression in several different types of breast cancer cell lines
Summary
Breast cancer is a malignant tumor that develops around breast tissue and has a high incidence and mortality among women [1]. With approximately 2.3 million newly diagnosed cases in 2020, breast cancer has become the most common type of cancer worldwide [2] This cancer type is considered manageable due to advancements in breast cancer treatment; more than 0.5 million patients lose their lives due to this malignancy annually [3]. Breast cancer development is frequently driven by epigenetic alterations, such as DNA methylation, microRNA expression modulation and histone modifications [4,5,6,7]. These epigenetic changes may influence protein-synthesis patterns and result in cancer development by inhibiting the tumor-suppressor gene and enhancing oncogene expression [8]. Among the various epigenetic modifiers, G9a has been suggested to exert oncogenic effects in multiple types of cancer [9]
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