N-methyladenosine-modified long non-coding RNA AGAP2-AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis.

Background: Psoriasis is a chronic, complicated, and recurrent inflammatory skin disease. However, the precise molecular mechanisms remain largely elusive and the present treatment is unsatisfactory.

Objective: This study aimed to unravel the functions of long noncoding RNA (lncRNA) AGAP2-AS1 and its biological mechanism in psoriasis pathogenesis, hinting for the new therapeutic targets in psoriasis.

Methods: The expression of AGAP2-AS1 in the skin tissue of psoriasis patients and healthy controls were detected by qRT-PCR and RNAscope®. Cell Counting Kit‑8 (CCK8) and clone formation assays were utilized to assess proliferation. Methylated RNA immunoprecipitation (MeRIP) was performed to detect the N-methyladenosine (mA) modification. RNA immunoprecipitation (RIP) was used to detect the interaction of AGAP2-AS1 with YTH domain family 2(YTHDF2). The relationships among AGAP2-AS1, miR-424-5p and AKT3 were examined by dual-luciferase reporter assay and RIP assay.

Results: We found that AGAP2-AS1 level was upregulated in the skin tissue of psoriasis patients than that of healthy controls and AGAP2-AS1 could promote proliferation and inhibit apoptosis of keratinocytes. Methyltransferase like 3(METTL3)-mediated m6A modification suppressed the expression of AGAP2-AS1 via YTHDF2-dependent AGAP2-AS1 stability. Thus, downregulation of METTL3 resulted in the upregulation of AGAP2-AS1 in psoriasis. AGAP2-AS1 functioned as a competitive endogenous RNA by sponging miR-424-5p to upregulate AKT3, activate AKT/mTOR pathway, as well as promote cell proliferation in keratinocytes.

Conclusion: AGAP2-AS1 is upregulated in the skin tissue of psoriasis patients and mA methylation was involved in its upregulation. AGAP2-AS1 promotes keratinocyte proliferation through miR-424-5p/AKT/mTOR axis and may be a promising target for psoriasis therapy.