Higher Order Chromatin Modulator Cohesin SA1 Is an Early Biomarker for Colon Carcinogenesis: Race-Specific Implications

Abstract

Alterations in high-order chromatin, with concomitant modulation in gene expression, are one of the earliest events in the development of colorectal cancer (CRC). Cohesins are a family of proteins that modulate high-order chromatin, although the role in CRC remains incompletely understood. We, therefore, assessed the role of cohesin SA1 in CRC biology and as a biomarker focusing in particular on the increased incidence/mortality of CRC among African-Americans (AAs). Immunohistochemistry on tissue arrays revealed dramatically decreased SA1 expression in both adenomas (62%; p=0.001) and adenocarcinomas (75%; p=0.0001). RT-PCR performed in endoscopically normal rectal biopsies (n=78) revealed a profound decrease in SA1 expression in adenoma-harboring patients (field carcinogenesis) compared to those who were neoplasia-free (47%; p=0.03). From a racial perspective, CRC tissues from Caucasians had 56% higher SA1 expression than in AAs. This was mirrored in field carcinogenesis where healthy Caucasians expressed more SA1 at baseline compared to matched AA subjects (73%; p=0.003). However, as a biomarker for CRC risk, the diagnostic performance as assessed by area under ROC curve was greater in AAs (AUROC=0.724) than Caucasians (AUROC=0.585). From a biological perspective, SA1 modulation of high-order chromatin was demonstrated with both biophotonic (nanocytology) and chromatin accessibility (MNase) assays in SA1-knockdown-HT29 CRC cells. The functional consequences were underscored by increased proliferation (WST-1; p=0.0002, colony formation; p=0.001) in the SA1-knockdown-HT29 cells. These results provide the first evidence indicating a tumor suppressor role of SA1 in early colon carcinogenesis and as a risk-stratification biomarker giving potential insights into biological basis of racial disparities in CRC.

The Global Relationship between Chromatin Physical Topology, Fractal Structure, and Gene Expression

“…nanoarchitecture). Indeed, the convergence of these molecular regulators on physical structure has been observed in studies of multiple chromatin remodelers (Supplemental Figure 1) and correlated with changes in accessibility1415. Therefore, while these descriptions are intuitive for the gene under exploration, they currently do not extend into an integrated model of chromatin physical topology.…”

Single Nucleotide Polymorphism Facilitated Down-Regulation of the Cohesin Stromal Antigen-1: Implications for Colorectal Cancer Racial Disparities

“…Furthermore, the racial predilection may explain, at least partly, the striking differences in CRC rates for Blacks compared to Whites. The patient database was small and thus the odds ratio for CRC was not significant but the decreased colonic SA-1 expression is compelling given the unequivocal data that SA-1 down-regulation is an earliest event in colon carcinogenesis [27] .…”

“…The cohesins, including SA-1 (also known as STAG1 and SCC3 ), are a recently discovered high order chromatin remodellors that are involved in chromatin looping (bringing enhancers/promoters in proximity to coding regions to foster transcription) and thus facilitate long-range nuclear interactions and gene expression [13] . While mutations in this family of proteins are rare in CRC, we have recently reported that SA-1 was significantly down-regulated in the endoscopically normal rectal mucosa of patients harboring adenomas elsewhere in their colon (field carcinogenesis) presumably through epigenetic mechanisms [14] . Moreover, SA-1 loss triggered critical pathways in carcinogenesis [15] , [16] , [17] .…”

The Transformation of the Nuclear Nanoarchitecture in Human Field Carcinogenesis

“…In this view, changes in DNA methylation (CpG islands), histone modifications, and mutations in both higher-order chromatin modulators (cohesins, condensins) and histone modifying enzymes (HDACs, SWItch/Sucrose nonfermentable enzymes) could be convergent on global changes that act at the level of a genomic ‘folding code’ [ 49–53 ]. Interestingly, PWS microscopy has shown that some of these alterations are manifested in transformation of the physical structure of chromatin [ 25 , 54 , 55 ].…”