Our results indicated that 6-TG inhibited cell proliferation and tumor cell progression by suppressing PI3K–AKT pathway via downregulating the DNA methylation level of PTEN. Moreover, apoptosis was induced via the activation of PI3K-AKT downstream TSC1 and the downregulation of methylation levels of DAXX, TNF, FADD and CASP8etc. These findings indicated 6-TG exerts its anti-tumor effects in vitro and in vivo through regulating the DNA methylation levels of genes involved in PI3K–AKT and apoptosis pathway. Here, TNF is linked to neoplasm.