Mavee Witherspoon

Weill Cornell Medical College, New York City, New York, United States

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Publications (10)99.09 Total impact

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    ABSTRACT: Unlabelled: The ornithine decarboxylase inhibitor α-difluoromethylornithine (DFMO) is a highly effective chemopreventive agent for colorectal cancer thought to act via polyamine depletion. However, in DFMO-treated patients, mucosal polyamine levels do not directly correlate with colorectal cancer risk. Untargeted metabolite profiling was used to broadly survey DFMO actions on colon cancer cell metabolism. We found that DFMO treatment of Apc(Min) intestinal tumors and human colorectal cancer cells is associated with reduced levels of folate-dependent metabolites, including S-adenosylmethionine (SAM), thymidine pools, and related pathway intermediates. We hypothesized that unrestrained SAM consumption/regeneration constitutes a futile DFMO-triggered cascade that can steal tetrahydrofolate from thymidylate synthase and thereby diminish thymidine pools. In accord with this hypothesis, DFMO treatment altered the folate cofactor balance and thymidine supplementation prevented DFMO-elicited cytostasis without restoring polyamine levels. These findings suggest that thymidine metabolite pool insufficiency is a fundamental mechanism of DFMO cytostatic activity. Significance: A previously unappreciated metabolic linkage between polyamine and thymidine biosynthesis is revealed, based on the competing requirement of these pathways for a limited pool of tetrahydrofolate cofactor. This study identifies the fi rst shared mechanism for colorectal cancer chemoprevention and chemotherapy, suggesting a common metabolic target for both premalignant and malignant colon cells.
    Preview · Article · Jun 2013 · Cancer Discovery
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    ABSTRACT: microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.
    Full-text · Article · May 2013 · Cell stem cell
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    ABSTRACT: Colorectal cancer is among the leading causes of cancer death in the USA. The polycomb repressive complex 2 (PRC2), including core components SUZ12 and EZH2, represents a key epigenetic regulator of digestive epithelial cell physiology and was previously shown to promote deleterious effects in a number of human cancers, including colon. Using colon cancer stem cells (CCSC) isolated from human primary colorectal tumors, we demonstrate that SUZ12 knockdown and treatment with DZNep, one of the most potent EZH2 inhibitors, increase apoptosis levels, marked by decreased Akt phosphorylation, in CCSCs, while embryonic stem (ES) cell survival is not affected. Moreover, DZNep treatments lead to increased PTEN expression in these highly tumorigenic cells. Taken together, our findings suggest that pharmacological inhibition of PRC2 histone methyltransferase activity may constitute a new, epigenetic therapeutic strategy to target highly tumorigenic and metastatic colon cancer stem cells.
    No preview · Article · Apr 2013 · Experimental Cell Research
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    ABSTRACT: Colorectal cancer is ranked among the top leading causes of cancer death in industrialized populations. Polycomb group proteins, including Suz12 and Ezh2, are epigenetic regulatory proteins that act as transcriptional repressors of many differentiation-associated genes and are overexpressed in a large subset of colorectal cancers. Retinoic acid (RA) acts as a negative regulator of PcG actions in stem cells, but has shown limited therapeutic potential in some solid tumors, including colorectal cancer, in part because of retinoic acid receptor β silencing. Through treatment with RA, Suz12 shRNA knockdown, or Ezh2 pharmacological inhibition with 3-deazaneplanocin A (DZNep), we increased TRAIL-mediated apoptosis in human colorectal cancer cell lines. This increased apoptosis in human colon cancer cells after RA or DZNep treatment was associated with a ∼2.5-fold increase in TNFRSF10B (DR5) transcript levels and a 42% reduction in the H3K27me3 epigenetic mark at the TNFRSF10B promoter after DZNep addition. Taken together, our findings indicate that pharmacological inhibition of Polycomb repressive complex 2 histone methyltransferase activity may constitute a new epigenetic therapeutic strategy to overcome RA non-responsiveness in a subset of colorectal tumors by increasing TRAIL-mediated apoptosis sensitivity. J. Cell. Physiol. 228: 764–772, 2013. © 2012 Wiley Periodicals, Inc.
    No preview · Article · Apr 2013 · Journal of Cellular Physiology

  • No preview · Conference Paper · Aug 2012

  • No preview · Article · May 2010 · Gastroenterology
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    ABSTRACT: Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for approximately 12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein alpha subunit Gialpha2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Gialpha2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Gialpha2-/- cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Gialpha2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Gialpha2-/- crypts. Treating Gialpha2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer.
    Full-text · Article · Aug 2009 · Cancer Research
  • Mavee S. Witherspoon · Kehui Wang · Steven M. Lipkin · Robert A. Edwards

    No preview · Article · May 2009 · Gastroenterology
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    ABSTRACT: Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is the most common known genetic syndrome for colorectal cancer (CRC). MLH1/MSH2 mutations underlie approximately 90% of Lynch syndrome families. A total of 24% of these mutations are missense. Interpreting missense variation is extremely challenging. We have therefore developed multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR), a bioinformatic algorithm that effectively classifies MLH1/MSH2 deleterious and neutral missense variants. We compiled a large database (n>300) of MLH1/MSH2 missense variants with associated clinical and molecular characteristics. We divided this database into nonoverlapping training and validation sets and tested MAPP-MMR. MAPP-MMR significantly outperformed other missense variant classification algorithms (sensitivity, 94%; specificity, 96%; positive predictive value [PPV] 98%; negative predictive value [NPV], 89%), such as SIFT and PolyPhen. MAPP-MMR is an effective bioinformatic tool for missense variant interpretation that accurately distinguishes MLH1/MSH2 deleterious variants from neutral variants.
    Full-text · Article · Jun 2008 · Human Mutation
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    ABSTRACT: E. coli AlkB has been intensively studied since 1983, but the in vivo roles of its mammalian homologue Alkbh1 are unknown. We, therefore, created null mice for Alkbh1. Alkbh1 mRNA is expressed at highest levels in the trophoblast lineages of the developing placenta. Alkbh1(-/-) placentas have decreased expression of differentiated trophoblast markers including Tpbp, Gcm1, and Pl-1, and increased expression of the trophoblast stem cell marker Eomes. Alkbh1 localizes to nuclear euchromatin, and interacts strongly with Mrj, an essential placental gene that mediates gene repression by recruitment of class II histone deacetylases (HDACs). Competition experiments show Alkbh1 and HDAC4 binding to Mrj are mutually exclusive, which causes decreased HDAC activity and increased target gene expression. Our study demonstrates Alkbh1 performs important functions in placental trophoblast lineage differentiation and participates in mechanisms of transcriptional regulation.
    Full-text · Article · Feb 2008 · Developmental Dynamics

Publication Stats

287 Citations
99.09 Total Impact Points


  • 2013
    • Weill Cornell Medical College
      • Department of Medicine
      New York City, New York, United States
  • 2008-2009
    • University of California, Irvine
      • • Department of Medicine
      • • Division of Hematology/Oncology
      Irvine, California, United States