Aberrant epigenetic regulation of RARβ by TET2 is involved in cutaneous squamous cell carcinoma resistance to retinoic acid

Objectives: With the growing incidence of cutaneous squamous cell carcinoma (CSCC), the treatment-resistant invasive CSCC should be taken seriously. Retinoic acid receptor beta (RAR beta) functions as a tumor suppressor gene and is associated with the proliferation inhibition to retinoic acid. Demethylase TET2 directed epigenetic landscape contributes to cell malignant transform and is involved in therapeutic resistance in tumors. Whether aberrant TET2 participated in the deficient RAR beta remains largely unknown. Hereby, we identified the aberrant-TET2 directed epigenetic landscape contribute to the deficient RAR beta in CSCC.& nbsp;Methods: The immunohistochemistry was used to detect the expression of RAR beta and TET2. The bisulfite sequencing PCR was used to detect the RAR beta promoter methylation. Plasmid transfection was used to upregulate TET2 in CSCC cells. Stable overxpressed TET2 cells were used to detect the effect of TET2 on RAR beta and drug sensitivity in the CCSC.& nbsp;Results: We observed RAR beta decreased with promoter hypermethylation in CSCC and aberrant TET2 associated with deficient RAR beta. We upregulated TET2 could reverse promoter hypermethylation and showed a significantly increased expression of RAR beta, which enhanced the sensitivity of tumor cells to retinoic acid treatment.& nbsp;Conclusion: Aberrant TET2 leaded to the hypermethylation of RAR beta promoter, which contributed to the deficient RAR beta in CSCC. While reversing the hypermethylation of the RAR beta promoter by recovering the TET2 could enhance tumor cells to be sensitive to retinoic acid.