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Suzuki K , Masuike Y , Mizuno R , Sachdeva UM , Chatterji P , Andres SF , Sun W , Klein-Szanto AJ , Besharati S , Remotti HE , Verzi MP , Rustgi AK
LIN28B induces a differentiation program through CDX2 in colon cancer
JCI Insight. 2021 Mar 23
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Abstract
Most colorectal cancers (CRCs) are moderately-differentiated or well-differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a novel post-transcriptional regulatory mechanism via a previously unappreciated LIN28B-CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration and tumorigenesis. Our RNA-binding protein immunoprecipitation (RIP) assay revealed LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression results in enhanced CDX2 expression to promote both differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. Chromatin immunoprecipitation (ChIP) sequence for CDX2 identified Alpha-Methylacyl-CoA racemase (AMACR) as a novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found AMACR enhances intestinal alkaline phosphatase (ALPi) activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrate that LIN28B promotes CRC differentiation through CDX2-AMACR axis.
Notes
2379-3708 Suzuki, Kensuke Masuike, Yasunori Mizuno, Rei Sachdeva, Uma M Chatterji, Priya Andres, Sarah F Sun, Wenping Klein-Szanto, Andres J Besharati, Sepideh Remotti, Helen E Verzi, Michael P Rustgi, Anil K Journal Article United States JCI Insight. 2021 Mar 23:140382. doi: 10.1172/jci.insight.140382.