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Cejas, Paloma; Cavazza, Alessia; Yandava, C. N.; Moreno, Victor; Horst, David; Moreno-Rubio, Juan; Burgos, Emilio; Mendiola, Marta; Taing, Len; Goel, Ajay; Feliu, Jaime; Shivdasani, Ramesh A. (2017): Transcriptional Regulator CNOT3 Defines an Aggressive Colorectal Cancer Subtype. In: Cancer Research, Vol. 77, No. 3: pp. 766-779
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Cancer cells exhibit dramatic alterations of chromatin organization at cis-regulatory elements, but the molecular basis, extent and impact of these alterations are still being unraveled. Here we identify extensive genome-wide modification of sites bearing the active histone mark H3K4me2 in primary human colorectal cancers (CRC), as compared to corresponding benign precursor adenomas. Modification of certain CRC sites highlighted the activity of the transcription factor CNOT3, which is known to control self-renewal of embryonic stem cells (ESC). In primary CRC cells, we observed a scattered pattern of CNOT3 expression, as might be expected for a tumor-initiating cell marker. CRC cells exhibited nuclear and cytoplasmic expression of CNOT3, suggesting possible roles in both transcription and mRNA stability. We found that CNOT3 was bound primarily to genes whose expression was affected by CNOT3 loss, and also at sites modulated in certain types of CRC. These target genes were implicated in ESC and cancer self-renewal and fell into two distinct groups: those dependent on CNOT3 and MYC for optimal transcription and those repressed by CNOT3 binding and promoter hypermethylation. Silencing CNOT3 in CRC cells resulted in replication arrest. In clinical specimens, early stage tumors that included >5% CNOT3(+) cells exhibited a correlation to worse clinical outcomes compared to tumors with little to no CNOT3 expression. Together, our findings implicate CNOT3 in the coordination of colonic epithelial cell self-renewal, suggesting this factor as a new biomarker for molecular and prognostic classification of early-stage CRC. (C) 2016 AACR.