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

Abstract

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 < 0.05). Exposure of human colon adenocarcinoma cells to LFMS microenvironment significantly hypomethylated Shh promoter region, activated Shh signaling, induced transcript and protein expressions of the pluripotent markers, promoted trans-differentiation as EMT by deregulation of Snail mediator and epithelial marker E-cadherin, increased MMP2/MMP9 enzymatic digestion on matrix protein for invasion, and promoted self-renewal capability of anchorage-independent tumor-spheroid formation. LFMS-induced cancer stem cell (CSC) signature and CRC invasion is synergized with inhibition of DNA methylation by 5-Aza-2-deoxycytidine (5AZA) in rewiring EMT genotypes, which can be blockade by the Shh inhibitor (cyclopamine). The in vivo and in vitro data corroboratively identify CSC-like molecular targets specific to the LFMS-predisposed invasive CRC through reprogramming DNA methylation-activated Shh signaling. The study highlights CSC targets specific to LFMS-predisposed invasive CRC in optimizing folate co-chemotherapy to minimize tumour metastasis potential of CRC patients.

Untargeted LC–MS/MS analysis reveals metabolomics feature of osteosarcoma stem cell response to methotrexate

“…Dissimilarities was observed in previous study, compared with our results, which might be the uniformity of definition and isolation techniques for CSCs [46]. In addition, the origins of CSCs within a cancer have not been clarified, oncogenic transformation from progenitor cells or normal tissue stem cells might be one of possible mechanisms [14], which might be accompanied with abnormal nucleic acid metabolism, such as DNA methylation [47] or RNA expression [48]. Moreover, one of the most important issues about cancer therapy is that increasing evidence has shown chemotherapeutic resistance in cancers, which is considered partially due to the existence of CSCs [14].…”

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

“…Folate is known to play an important role in human health and disease due to its participation in diverse metabolic pathways as well as in the regulation of methylation reactions. Pleiotropic effects of folate in cancer cells have been linked to migratory capacity and invasiveness; though effects may differ by cancer type, stage and molecular subtype [50,61,62]. We have previously shown that folic acid withdrawal resulted in metabolic and bioenergetic changes indicative of a less proliferative as well as less migratory phenotype in mouse TNBC cell lines [50].…”

Folate can promote the methionine-dependent reprogramming of glioblastoma cells towards pluripotency

“…Altered folate metabolism has indeed been implicated in promoting cancer stem cell formation. For example, low folate was linked to pluripotent gene expression via sonic hedgehog or Akt-mTOR-HIF1-FOXO3a pathways in colorectal 30 and lung cancer 31 . Similarly, 5-MethylTetraHydroFolate down-regulation was observed during reprogramming of mouse embryonic fibroblasts (MEFs) into mouse induced pluripotent cells (iPSC) 32 .…”