LIN28B inhibition sensitizes cells to p53-restoring PPI therapy through unleashed translational suppression

p53 is the most highly mutated tumor suppressor across multiple types of human cancers. The level and function of p53 are fine-tuned through multifaced mechanisms in which the protein-protein interaction between p53 and MDM2 is considered as a major circuit. Recent studies suggest therapeutic strategy attempts to restore p53 function by small molecule inhibitors targeting p53-MDM2 interaction can be a promising direction in treating cancers with wild-type or functional p53. Currently, clinical tests of the p53-MDM2 protein-protein interaction inhibitors (PPIs) are underway. However, it remains elusive about the biomarkers that may predict the therapeutic responses to those inhibitors. Here we report that RNA-binding protein LIN28B directly regulates p53 through binding to the 5 ' GREEK TONOS untranslated region of p53 mRNA and blocks its translation by competing with a translation enhancer protein, ribosomal protein L26 (RPL26). This regulatory mechanism of LIN28B does not involve let-7 maturation or the canonical protein turnover pathway of p53. Furthermore, we show that inhibition of LIN28B unleashes the translational suppression of p53 through RPL26, and leads to enhanced sensitivities of cancer cells to inhibitors of p53-MDM2 interaction. Together, we demonstrate a competitive regulatory mechanism of p53 by LIN28B, which has important implications in developing biomarkers to the therapies aiming to reinstate p53 function.

Automated summary

p53 is the most highly mutated tumor suppressor in various human cancers, and its function is modulated through protein-protein interaction with MDM2. Restoring p53 function by inhibiting p53-MDM2 interaction is a promising therapeutic strategy for cancers with wild-type or functional p53. However, the biomarkers that can predict the response to these inhibitors remain elusive. In this study, LIN28B was found to directly regulate p53 by binding to its mRNA and inhibiting translation through competition with RPL26. Inhibition of LIN28B releases p53 translation suppression and enhances cancer cell sensitivities to p53-MDM2 inhibitors. These findings have important implications in developing biomarkers for therapies targeting p53 function.