Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer

Peng, Shuping; Maihle, Nita J.; Huang, Yu‐Sheng

doi:10.1038/onc.2009.500

Cited by 234 publications

(204 citation statements)

References 33 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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“…Several studies have reported that LIN28A may serve as an oncogene, promoting malignant transformation (42,43,52,53), inducing metastasis (43,46,(52)(53)(54), regulating inflammation (5,43), and maintaining the cancer stem cells (43,45,(55)(56)(57). However, the function and molecular mechanism of LIN28A in cell cycle regulation of cancer cells is still largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that both expression of LIN28A and LIN28B are reac- (4,(42)(43)(44)(45)(46)(47). However, the expression and distribution of LIN28A in different types of epithelial tumors is still unknown.…”

Section: Reactivation Of Strong Lin28a Expression In 10% Of Humanmentioning

confidence: 99%

“…Recent studies in cancer also found that knocking down LIN28A expression in cancer cell lines can remarkably reduce cancer cell viability and inhibit cell growth in vitro (42,45,62). These findings led to a hypothesis that in cancer cells, LIN28A may have a similar function as in ES cells to regulate the cell cycle.…”

mentioning

confidence: 97%

“…Importantly, the expression of LIN28A/LIN28B is highly restricted to ES cells and developing tissues, and expression dramatically decreases as differentiation progresses (2,3,7,8,11,21,40,41). In human tumors, LIN28A/LIN28B expression is up-regulated/reactivated (4,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) and may function as an oncogene promoting malignant transformation (42,43,52,53), inducing metastasis (43,46,(52)(53)(54), regulating inflammation (5,43), and maintaining the cancer stem cells (43,45,(55)(56)(57). Clinical studies have indicated that higher levels of LIN28A/LIN28B expression are associated with poor clinical outcomes (44,58,59) and that LIN28 family polymorphisms may influence susceptibility to ovarian (60) and breast (61) cancers.…”

mentioning

confidence: 99%

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Lin-28 Homologue A (LIN28A) Promotes Cell Cycle Progression via Regulation of Cyclin-dependent Kinase 2 (CDK2), Cyclin D1 (CCND1), and Cell Division Cycle 25 Homolog A (CDC25A) Expression in Cancer

Zhong

Lin

et al. 2012

Journal of Biological Chemistry

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Background: LIN28A may function as a critical oncogene in human cancer. Results: LIN28A controls expression of numerous cell cycle regulatory genes, including CDK2, CCND1, and CDC25A, in cancer. Conclusion: LIN28A promotes cell cycle progression in cancer mediated by both let-7-dependent and -independent mechanisms. Significance: Our data shed new light on how LIN28A regulates cell cycle in cancer.

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