Abstract
BackgroundLin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, although they target separate steps in the maturation of let-7 miRNAs in mammalian cells. Because Lin28B participates in the promotion and development of tumors mostly by blocking the let-7 tumor suppressor family members, we sought to explore the associated mechanisms to gain insights into how Lin28B might be decreased in human cancer cells to increase let-7 levels and reverse malignancy.ResultsWe demonstrated that the histone acetyltransferase PCAF, via its cold shock domain, directly interacts with and subsequently acetylates Lin28B in lung adenocarcinoma-derived H1299 cells. RT-qPCR assays showed that both let-7a-1 and let-7g were increased in PCAF-transfected H1299 cells. Lin28B is acetylated by ectopic PCAF and translocates from the nucleus to the cytoplasm in H1299 cells.ConclusionsThe effects of acetylated Lin28B on let-7a-1 and let-7g are similar to that of stable knockdown of Lin28B in H1299 cells. The new role of PCAF in mediating Lin28B acetylation and the specific release of its target microRNAs in H1299 cells may shed light on the potential application of let-7 in the clinical treatment of lung cancer patients.
Highlights
Lin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, they target separate steps in the maturation of let-7 miRNAs in mammalian cells
The effect of Lin28B knockdown on let-7 expression in H1299 cells Consistent with the literature [8], Lin28B is mainly found to be distributed in the nucleus (Fig. 1a), where it abrogates the expression of let-7 miRNA
We found that the expression of the Lin28B protein (Fig. 1b) and its mRNA (Fig. 1c) was lower in the Lin28Bknockdown cells (Lin28B-K/D) than in cells mock transduced with shRNA against luciferase
Summary
Lin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, they target separate steps in the maturation of let-7 miRNAs in mammalian cells. Because Lin28B participates in the promotion and development of tumors mostly by blocking the let-7 tumor suppressor family members, we sought to explore the associated mechanisms to gain insights into how Lin28B might be decreased in human cancer cells to increase let-7 levels and reverse malignancy. In eukaryotes including worms and mammals, Lin blocks let-7 expression, whereas let-7 negatively regulates Lin expression by binding to the 3’UTR of Lin mRNA, thereby establishing a double negative feedback loop. The Lin28/let-7 axis plays a pivotal role in stem cell biology and the development and control of glucose metabolism, as well as in human diseases [4, 5]. There are two Lin paralogs: Lin28A and Lin28B. Lin28B has a coding extended C terminus that contains a nuclear
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