Low folate metabolic stress reprograms DNA methylation-activated sonic hedgehog signaling to mediate cancer stem cell-like signatures and invasive tumour stage-specific malignancy of human colorectal cancers.

The mechanistic role of colonic low folate metabolic stress (LFMS) in colorectal cancer (CRC) malignancy development remains unknown. Folate analysis on the 99 paired human CRC tissues localized LFMS to the deep invasive T3/T4 staged tumours with hypo-methylated sonic hedgehog (Shh) promoter region and amplified expressions of Shh ligand and Gli1 effector, which coincided with deregulated expressions of the epithelial-mesenchymal transition (EMT) mediators. Colonic folate levels of CRC were inversely correlated with pluripotent expressions of the SOX2, NANOG and OCT4 markers (p < 0.