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Summary: The diversity and complexity of the cancer transcriptome may contain transcripts unique to the tumor environment. Here, we report a LIN28B variant, LIN28B-TST, which is specifically expressed in hepatocellular carcinoma (HCC) and many other cancer types. Expression of LIN28B-TST is associated with significantly poor prognosis in HCC patients. LIN28B-TST initiates from a de novo alternative transcription initiation site that harbors a strong promoter regulated by NFYA but not c-Myc. Demethylation of the LIN28B-TST promoter might be a prerequisite for its transcription and transcriptional regulation. LIN28B-TST encodes a protein isoform with additional N-terminal amino acids and is critical for cancer cell proliferation and tumorigenesis. Our findings reveal a mechanism of LIN28B activation in cancer and the potential utility of LIN28B-TST for clinical purposes.

Contact inhibition of proliferation is critical for tissue organization, and its dysregulation contributes to tumorigenesis. Merlin/NF2 is a tumor suppressor that governs contact inhibition. Although Merlin/NF2 inhibits YAP1 and TAZ, which are paralogous Hippo pathway transcriptional co-activators and oncoproteins, it is not fully understood how Merlin/NF2-mediated signal transduction triggered by cell-cell contact exerts tumor suppression. Here, we identify Lin28B, an inhibitor of let-7 microRNAs (miRNAs), as an important downstream target of Merlin/NF2. Functional studies revealed that, at low cell density, Merlin/NF2 is phosphorylated and does not bind to Lin28B, allowing Lin28B to enter the nucleus, bind to pri-let-7 miRNAs, and inhibit their maturation in a YAP1/TAZ-independent manner. This inhibition of pri-let-7 maturation then promotes cell growth. However, cell-cell contact triggers Merlin/NF2 dephosphorylation, which sequesters Lin28B in the cytoplasm and permits pri-let-7 maturation. Our results reveal that Merlin/NF2-mediated signaling drives a tumor-suppressive pathway that is cell-density dependent and Hippo independent.

Summary Contact inhibition of proliferation is critical for tissue organization, and its dysregulation contributes to tumorigenesis. Merlin/ NF2 is a tumor suppressor that governs contact inhibition. Although Merlin/ NF2 inhibits YAP1 and TAZ, which are paralogous Hippo pathway transcriptional co-activators and oncoproteins, it is not fully understood how Merlin/ NF2 -mediated signal transduction triggered by cell-cell contact exerts tumor suppression. Here, we identify Lin28B, an inhibitor of let-7 microRNAs (miRNAs), as an important downstream target of Merlin/ NF2 . Functional studies revealed that, at low cell density, Merlin/ NF2 is phosphorylated and does not bind to Lin28B, allowing Lin28B to enter the nucleus, bind to pri- let-7 miRNAs, and inhibit their maturation in a YAP1/TAZ-independent manner. This inhibition of pri- let-7 maturation then promotes cell growth. However, cell-cell contact triggers Merlin/ NF2 dephosphorylation, which sequesters Lin28B in the cytoplasm and permits pri- let-7 maturation. Our results reveal that Merlin/ NF2 -mediated signaling drives a tumor-suppressive pathway that is cell-density dependent and Hippo independent. [ABSTRACT FROM AUTHOR]

MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r can be sufficient to drive transformation. However, despite the prenatal origin of MLL-r in these patients, congenital leukemia is very rare with transformation usually occurring postnatally. The influence of prenatal signals on leukemogenesis, such as those mediated by the fetal-specific protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that co-expresses MLL-ENL and LIN28B, we investigate the impact of LIN28B on AML. LIN28B impedes the progression of MLL-r AML through compromised leukemia-initiating cell activity and suppression of MYB signaling. Mechanistically, LIN28B directly binds to MYBBP1A mRNA, resulting in elevated protein levels of this MYB co-repressor. Functionally, overexpression of MYBBP1A phenocopies the tumor-suppressor effects of LIN28B, while its perturbation omits it. Thereby, we propose that developmentally restricted expression of LIN28B provides a layer of protection against MYB-dependent AML. [Display omitted] • LIN28B does not become re-activated in human or murine AML • The expression of LIN28B suppresses MLL-ENL-driven AML • LIN28B compromises leukemic development by suppressing MYB activity • The tumor-suppressor effects of LIN28B are largely driven by MYBBP1A Eldeeb et al. report an LIN28B-mediated molecular layer of protection against perinatal AML. LIN28B expression associates with attenuated MYB activity driven by positive regulation of MYBBP1A. These insights into the roles of LIN28B can be exploited for therapeutic benefits. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fueling the search for alternative approaches. Here, we show that the oncofetal RNA-binding protein LIN28B regulates the stability of EWS-FLI1 mRNA in ~10% of EwSs. LIN28B depletion in these tumors leads to a decrease in the expression of EWS-FLI1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of LIN28B mimics the effect of LIN28B depletion, suggesting that LIN28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target. • Lin28B expression identifies a subset of Ewing sarcomas • Lin28B binds and stabilizes EWS-FLI-1 transcripts in these tumors • Depletion or inhibition of Lin28B results in the deconstruction of the tumors • Lin28B may provide a therapeutic target in a subset of Ewing sarcomas Keskin et al. show that Lin28B directly binds EWS-FLI-1 and maintains its stability in ~10% of Ewing sarcomas. Lin28B depletion or its chemical inhibition in these tumors results in the loss of EWS-FLI-1 expression and tumor deconstruction. Lin28B may provide an attractive therapeutic target in a subset of Ewing sarcomas. [ABSTRACT FROM AUTHOR]