A role for Lin28 in primordial germ-cell development and germ-cell malignancy

West, Jason A.; Viswanathan, Srinivas R.; Yabuuchi, Akiko; Cunniff, K. C.; Takeuchi, Akari; Park, In‐Hyun; Sero, Julia E.; Zhu, Min; Perez‐Atayde, Antonio R.; Frazier, A. Lindsay; Surani, M. Azim; Daley, George Q.

doi:10.1038/nature08210

Cited by 349 publications

(379 citation statements)

References 40 publications

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“…Lin28A/B expression is associated with advanced disease in hepatocellular carcinoma (HCC), chronic myeloid leukemia (CML), Wilms' tumor, ovarian carcinoma, and germ cell tumors. 16,22,[35][36][37][38][39][40][41][42][43][44] Moreover, Lin28A/Lin28B expression is associated with poor clinical outcome and patient survival in HCC, ovarian cancer, Neuroblastoma, and Medulloblastoma. 16,18,35,45 Therefore, identification of small molecule drugs that specifically inhibit the Lin28/ let-7 pathway might prove to be a powerful approach for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Identification of small molecule inhibitors of Zcchc11 TUTase activity

Lin

Gregory

2015

RNA Biology

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The RNA-binding protein Lin28 regulates the expression of the let-7 family of microRNAs (miRNAs) during early embryonic development. Lin28 recruits the 3 0 terminal uridylyl transferase (TUTase) Zcchc11 (TUT4) and/or Zcchc6 (TUT7) to precursor let-7 RNA (pre-let-7) to selectively block let-7 biogenesis. Uridylated pre-let-7 is targeted for decay by the downstream exonuclease Dis3l2 thereby preventing processing to mature let-7. Activation of this oncogenic pathway via up-regulation of Lin28 expression promotes cellular transformation, drives tumorigenesis in mouse models, and is frequently observed in a wide variety of cancer. Recent proof-of-principle experiments showed that Zcchc11 knockdown inhibits the tumorigenicity of Lin28-expressing human cancer cells and established this enzyme as a possible new therapeutic target for human malignancies. However, there are currently no known pharmacological agents capable of targeting this novel enzyme. In this study we developed and applied a sensitive biochemical assay that monitors Zcchc11 activity. Using this assay we performed an automated high-throughput screen of »15,000 chemicals to identify putative TUTase inhibitors. Several of these small molecules were validated as specific inhibitors of Zcchc11 activity. Our results demonstrate the feasibility of screening for TUTase inhibitors and present a relatively simple platform that can be exploited for future drug discovery efforts aimed at restoring let-7 expression in cancer.

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Section: Discussionmentioning

confidence: 99%

Identification of small molecule inhibitors of Zcchc11 TUTase activity

Lin

Gregory

2015

RNA Biology

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“…In line with our findings, Blimp-1/prdm1 was demonstrated by elegant genetic experiments to be an in vivo target for let-7 in primordial germ-cell development in mice. 31 Down-regulation of PRDM1 by let-7 appears to be mediated by translation inhibition. 12 Although let-7 has also been shown to be able to promote mRNA degradation, 32 this effect may be dependent on target genes and cell types.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

Nie

Zhang

Allawi

et al. 2010

The American Journal of Pathology

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PRDM1/Blimp-1, a master regulator for B cell terminal differentiation, is a putative tumor suppressor in diffuse large B cell lymphomas (DLBCL). Inactivating mutations of PRDM1 have been previously identified in a subset of nongerminal center B cell-like (GCB) DLBCL. We investigated the presence of alternative mechanisms of down-regulating PRDM1 in a cohort of 25 primary DLBCL and six DLBCL cell lines. While some DLBCL, predominantly the GCB-type, showed low levels of both PRDM1␣ mRNA and protein, presumably as a result of direct transcription repression, discordant expressions between the two were identified in a subset of DLBCL without PRDM1 mutations, the primarily non-GCB type, consistent with translational down-regulation. This subset of DLBCL exhibits relatively high PRDM1␣ mRNA levels but low levels of PRDM1. Data obtained from expression analysis , luciferase reporter assays , and transfection experiments support a role of targeting of PRDM1 by microRNA let-7 family in mediating this down-regulation. Let-7 , in particular let-7b , is overexpressed in DLBCL relative to normal GCB cells , suggesting that it is deregulated. Thus , abnormal epigenetic down-regulation of PRDM1 by let-7 and other microRNAs may represent an alternative mechanism of reducing normal PRDM1 function in a subset of DLBCL with relatively high PRDM1␣ mRNA expression and unmutated PRDM1. PRDM1/Blimp-1 is a master transcriptional regulator for terminal differentiation of B cells into plasma cells. [1][2][3][4] It also plays a critical role in effector and memory T-cell differentiation, 1,3,5 myeloid cell development, 6 dendritic cell development, 7 and epithelial cell differentiation. 8 Inactivating mutations that result in the generation of a severely truncated nonfunctional PRDM1 are found in about 20% of the diffuse large B cell lymphomas (DLBCLs) of the nongerminal center B cell (GCB) subtype 9,10 and also in about 19% of the primary DLBCL of the central nervous system. 11 These mutations are associated with deletion of the other paired PRDM1 allele at chromosome 6q21. These findings are consistent with PRDM1 being a DLBCL tumor suppressor gene and imply an important role of impairment of terminal B cell differentiation in DLBCL pathogenesis. However, many DLBCLs lack genetic alterations in PRDM1. Posttranscriptional down-regulation of PRDM1 in DLBCL has been suggested, but no systematic evaluation was performed. 10 In this study, we investigated this possibility in detail by comparative and quantitative analysis of PRDM1 mRNA and protein expression in different subgroups of DLBCL. We concluded that low or absent PRDM1 expression is a common phe-

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“…Of the 53 genes that were higher in PSC derivatives (in red), 22 were also strongly expressed in undifferentiated PSCs relative to somatic cells (indicated with asterisk). This list included LIN28B, DPPA4, and TCF7L1 (TCF3), all of which are known to play a role in ESCs and in very early mammalian development [28,[30][31][32][33]. Furthermore, 35 genes were downregulated in PSC derivatives compared to tissue-derived cells (in green), perhaps reflecting a state of incomplete specification, regardless of the cell type generated.…”

Section: Psc Derivatives and Tissue-derived Counterparts Are Distingumentioning

confidence: 99%

Defining the nature of human pluripotent stem cell progeny

et al. 2011

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While it is clear that human pluripotent stem cells (hPSCs) can differentiate to generate a panoply of various cell types, it is unknown how closely in vitro development mirrors that which occurs in vivo. To determine whether human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) make equivalent progeny, and whether either makes cells that are analogous to tissue-derived cells, we performed comprehensive transcriptome profiling of purified PSC derivatives and their tissue-derived counterparts. Expression profiling demonstrated that hESCs and hiPSCs make nearly identical progeny for the neural, hepatic, and mesenchymal lineages, and an absence of re-expression from exogenous reprogramming factors in hiPSC progeny. However, when compared to a tissuederived counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated. While pluripotent genes (OCT4, SOX2, REX1, and NANOG) appeared to be silenced immediately upon differentiation from hPSCs, genes normally unique to early embryos (LIN28A, LIN28B, DPPA4, and others) were not fully silenced in hPSC derivatives. These data and evidence from expression patterns in early human fetal tissue (3-16 weeks of development) suggest that the differentiated progeny of hPSCs are reflective of very early human development (< 6 weeks). These findings provide support for the idea that hPSCs can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical application of hPSC derivatives.

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A role for Lin28 in primordial germ-cell development and germ-cell malignancy

Cited by 349 publications

References 40 publications

Identification of small molecule inhibitors of Zcchc11 TUTase activity

Identification of small molecule inhibitors of Zcchc11 TUTase activity

Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas

Defining the nature of human pluripotent stem cell progeny

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