Chawla Ayesha T, Cororaton Agnes D, Idowu Michael O, Damle Priyadarshan K, Szomju Barbara, Ellis Keith C, Patel Bhaumik B, Grossman Steven R
VCU Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA.
Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
Oncotarget. 2018 Aug 21;9(65):32408-32418. doi: 10.18632/oncotarget.25784.
C-terminal binding protein 2 (CtBP2) drives intestinal polyposis in the mouse model of human Familial Adenomatous Polyposis. As CtBP2 is targetable by an inhibitor of its dehydrogenase domain, understanding CtBP2's role in adenoma formation is necessary to optimize CtBP-targeted therapies in mutated human neoplasia. Tumor initiating cell (TIC) populations were substantially decreased in intestinal epithelia. Moreover, normally nuclear Ctbp2 was mislocalized to the cytoplasm of intestinal crypt stem cells in mice, both and wildtype, correlating with low/absent CD133 expression in those cells, and possibly explaining the lower burden of polyps in Ctbp2 mice. The CtBP inhibitor 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) also robustly downregulated TIC populations and significantly decreased intestinal polyposis in mice. We have therefore demonstrated a critical link between polyposis, intestinal TIC's and gene dosage or activity, supporting continued efforts targeting CtBP in the treatment or prevention of mutated neoplasia.
C末端结合蛋白2（CtBP2）在人类家族性腺瘤性息肉病的小鼠模型中引发肠道息肉病。由于CtBP2可被其脱氢酶结构域的抑制剂靶向，了解CtBP2在腺瘤形成中的作用对于优化针对突变人类肿瘤的CtBP靶向治疗至关重要。肿瘤起始细胞（TIC）群体在肠上皮细胞中显著减少。此外，在野生型和突变型小鼠中，正常定位于细胞核的Ctbp2都错误定位于肠隐窝干细胞的细胞质中，这与这些细胞中低表达或不表达CD133相关，这可能解释了Ctbp2突变小鼠中息肉负担较低的原因。CtBP抑制剂4-氯-羟基亚氨基苯丙酮酸（4-Cl-HIPP）也能强力下调TIC群体，并显著减少小鼠的肠道息肉病。因此，我们证明了息肉病、肠道TIC与基因剂量或活性之间的关键联系，支持在治疗或预防突变肿瘤方面继续努力靶向CtBP。
