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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
Author(s) -
Feng HsinChun,
Lin JhuanYu,
Hsu ShuHan,
Lan WenYu,
Kuo ChangSheng,
Tian YuFeng,
Sun DingPing,
Huang RweiFen Syu
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31008
Subject(s) - cancer research , cyclopamine , sonic hedgehog , dna methylation , gli1 , sox2 , hedgehog signaling pathway , biology , gli2 , cancer , reprogramming , cancer stem cell , colorectal cancer , epithelial–mesenchymal transition , metastasis , stem cell , microbiology and biotechnology , signal transduction , cell , embryonic stem cell , genetics , gene expression , gene
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.