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 β (RARβ) 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 RARβ remains largely unknown. Hereby, we identified the aberrant-TET2 directed epigenetic landscape contribute to the deficient RARβ in CSCC.

Methods: The immunohistochemistry was used to detect the expression of RARβ and TET2. The bisulfite sequencing PCR was used to detect the RARβ 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 RARβ and drug sensitivity in the CCSC.

Results: We observed RARβ decreased with promoter hypermethylation in CSCC and aberrant TET2 associated with deficient RARβ. We upregulated TET2 could reverse promoter hypermethylation and showed a significantly increased expression of RARβ, which enhanced the sensitivity of tumor cells to retinoic acid treatment.

Conclusion: Aberrant TET2 leaded to the hypermethylation of RARβ promoter, which contributed to the deficient RARβ in CSCC. While reversing the hypermethylation of the RARβ promoter by recovering the TET2 could enhance tumor cells to be sensitive to retinoic acid.