TY - JOUR
T1 - LIN28B induces a differentiation program through CDX2 in colon cancer
AU - Suzuki, Kensuke
AU - Masuike, Yasunori
AU - Mizuno, Rei
AU - Sachdeva, Uma M.
AU - Chatterji, Priya
AU - Andres, Sarah F.
AU - Sun, Wenping
AU - Klein-Szanto, Andres J.
AU - Besharati, Sepideh
AU - Remotti, Helen E.
AU - Verzi, Michael P.
AU - Rustgi, Anil K.
N1 - Funding Information:
We wish to thank members of the Rustgi lab, Piero Dalerba, and Irwin J. Kurland for helpful discussions. This work was supported by NIH DK-566645, NCI P30-CA013696, American Gastroenterological Association Research Scholar Award (to SFA), and Honjo International Scholarship Foundation (to KS). We wish to acknowledge the following shared resources: the Molecular Pathology Core, Confocal and Specialized Microscopy, Oncology Precision Therapeutics and Imaging Core (OPTIC) at the Herbert Irving Comprehensive Cancer Center of Columbia University Irving Medical Center, and the Stable Isotope & Metabolomics Core at Diabetes Research Center of Albert Einstein College of Medicine. The graphical abstract was created with BioRender.
Publisher Copyright:
© 2021, Suzuki et al.
PY - 2021/5/10
Y1 - 2021/5/10
N2 - 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 potentially novel posttranscriptional regulatory mechanism via a 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 RNAbinding protein IP (RIP) assay revealed that LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression resulted in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. A ChIP sequence for CDX2 identified a-methylacyl-CoA racemase (AMACR) as a potentially novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found that AMACR enhanced intestinal alkaline phosphatase activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrated that LIN28B promotes CRC differentiation through the CDX2/AMACR axis.
AB - 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 potentially novel posttranscriptional regulatory mechanism via a 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 RNAbinding protein IP (RIP) assay revealed that LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression resulted in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. A ChIP sequence for CDX2 identified a-methylacyl-CoA racemase (AMACR) as a potentially novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found that AMACR enhanced intestinal alkaline phosphatase activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrated that LIN28B promotes CRC differentiation through the CDX2/AMACR axis.
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U2 - 10.1172/jci.insight.140382
DO - 10.1172/jci.insight.140382
M3 - Article
C2 - 33755595
AN - SCOPUS:85105937714
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 9
M1 - e140382
ER -