A regulatory circuitry comprising TP53, <i>miR-29</i> family, and SETDB1 in non-small cell lung cancer

Abstract

Lung cancer is a malignant tumor with high fatality rate and causes great harm to human economic life. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. With the rapid development of epigenetic study in the last decade, the understanding of the pathogenesis of lung cancer and the development of personalized treatment of lung cancer are picking up pace. Previous studies showed that <i>miR-29</i> family members (<i>miR-29s</i>; <i>miR-29a, -29b</i>, and <i>-29c</i>) are down-regulated in most human cancers, including NSCLC, but their biological roles in tumorigenesis and their regulation mechanism are still not fully elucidated. Herein, we reported that the <i>miR-29a, -29b</i> and, <i>-29c</i> were coincidently down-regulated in NSCLC, and the histone H3K9 methyltransferase SET domain, bifurcated 1 (SETDB1) was directly targetted by <i>miR-29s</i> Moreover, SETDB1 negatively regulated the expression of TP53 and overexpression of SETDB1 down-regulating the expression of <i>miR-29s</i>, while TP53 positively regulated the expression of <i>miR-29s</i> and overexpression of TP53 down-regulated the expression of SETDB1. On the other side, as a downstream target of TP53, the H3K9 methyltransferase Suv39h1 was also down-regulated by <i>miR-29s</i> via up-regulating TP53 expression. The further detection of H3K9 methylation status after changes in <i>miR-29s</i> expression revealed that they negatively regulated the levels of H3K9 di- and trimethylation in NSCLC. Collectively, our findings highlight a TP53/<i>miR-29s</i>/SETDB1 regulatory circuitry and assign a role of H3K9 methylation regulator to <i>miR-29s</i>, which may be a potential therapeutic target in the treatment of NSCLC.