Lin28A and Lin28B Inhibit let-7 MicroRNA Biogenesis by Distinct Mechanisms

Abstract

Lin28A and Lin28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. Lin28A recruits a TUTase (Zcchc11/TUTase4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike Lin28A, Lin28B represses let-7 processing through a TUTase-independent mechanism. Lin28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts is restricted to Lin28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either Lin28A or Lin28B. Lin28A is expressed in HER2-overexpressing breast tumors while Lin28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which Lin28A and Lin28B function, and have implications for the development of new strategies for cancer therapy.

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

“…A recent study had suggested that BDNF can regulate the protein levels of miRNA-processing factor Lin-28 homolog A (LIN28A) (43), a protein known to affect the maturation of the let-7 family of miRNAs (44). We found a greater than twofold reduction in LIN28A protein in the cerebellum of Mecp2 KO mice, suggesting that miRNA processing might be perturbed (Fig.…”

“…Despite the fact that BDNF-LIN28A, LIN28A-let-7, and let7f-IGF1 interactions have independently been verified in different systems (43)(44)(45), our study provides additional in vivo correlative and in vitro mechanistic evidence of a linear pathway downstream of BDNF that involves all four molecular components (Fig. 4D).…”

The long intergenic non-coding RNA CCR492 functions as a let-7 competitive endogenous RNA to regulate c-Myc expression

“…In spite of their different genome organization let-7 precursors share conserved structural elements and the sequence of the mature microRNA is highly conserved. One way to regulate let-7 expression is by Lin28 proteins which inhibit the mature form by their specific interaction with let-7 precursors [27][28][29]. Another simple and effective way to regulate let-7 function is to inhibit their activity by direct interaction with the mature microRNAs as all let-7 genes share the same seed to bind to their targets.…”

Identification of small molecule inhibitors of Zcchc11 TUTase activity

“…[23][24][25][26][27] TUTase activity is required for the Lin28-mediated inhibition of let-7 biogenesis, and RNAi-mediated knockdown of Zcchc11 has been shown to inhibit tumorigenesis of human breast, ovarian, melanoma, prostate, and liver cancer cells in mouse xenograft assays. 28,29 Moreover, Zcchc11 knockdown inhibited the lung metastasis of liver cancer cells. 29 In addition, Zcchc11 expression was found to be up-regulated in primary human liver and colorectal tumors compared with matched normal tissues.…”