N6-methyladenosine-modified long non-coding RNA AGAP2-AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis

作者：Xian, Jiayi; Shang, Mingwei; Dai, Yu; Wang, Qi; Long, Xinxin; Li, Jiazheng; Cai, Yantao^*; Xia, Chenglai^*; Peng, Xuebiao^*

来源：Journal of Dermatological Science, 2022, 105(1): 27-36.

DOI：10.1016/j.jdermsci.2021.11.007

• AGAP2-AS1
• Psoriasis
• M(6)A
• MiR-424-5p
• AKT3

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 (R). Cell Counting Kit-8 (CCK8) and clone formation assays were utilized to assess proliferation. Methylated RNA immunoprecipitation (MeRIP) was performed to detect the N-6-methyladenosine (m(6)A) 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 m(6)A 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.

• 单位
  南方医科大学