PLAA suppresses ovarian cancer metastasis via METTL3-mediated m6A modification of TRPC3 mRNA

Abstract

Wide metastasis contributes to a high death rate in ovarian cancer, and understanding of the molecular mechanism helps to find effective targets for metastatic ovarian cancer therapy. It has been found that phospholipase A2-activating protein (PLAA) is inactivated in some cancers, but its role in cancer metastasis remains unknown. Here, we found that PLAA was significantly downregulated in ovarian cancer highly metastatic cell lines and patients, and the low expression of PLAA was associated with poorer prognosis and high-risk clinicopathological features of patients. PLAA inhibited the migration and invasion of ovarian cancer cells and metastasis of transplanted tumor in the orthotopic xenograft mouse model. Meanwhile, PLAA inhibited metastasis of ovarian cancer by inhibiting transient receptor potential channel canonical 3 (TRPC3)-mediated the intracellular Ca2+ level. Mechanistically, PLAA inhibited methyltransferase-like 3 (METTL3) expression through the ubiquitin-mediated degradation, and METTL3 stabilized TRPC3 mRNA expression via N6-methyladenosine (m6A) modification. Our study verified the function and mechanism of the PLAA-METTL3-TRPC3 axis involved in ovarian cancer metastasis, with a view to providing a potential therapeutic approach for ovarian cancer.

Interactions of Histone Deacetylase 6 with DNA Damage Repair Factors Strengthen its Utility as a Combination Drug Target in High-Grade Serous Ovarian Cancer

“…In the CD2 condition, there is evidence of a higher confidence interaction between HDAC6 and PLAA, which has been previously associated with the suppression of ovarian cancer metastasis. 60 In addition to XRCC6, GEMIN5 and PFKL were shared first neighbors under the CD1 and CD2 mutant conditions. ACTG1 was the only first neighbor that was shared between CD1 and CD1/2 (Figure 2A,C).…”

The landscape of m6A regulators in esophageal cancer: molecular characteristics, immuno-oncology features, and clinical relevance

“…After cleaning the inner membrane of the upper chamber with a cotton swab, images were observed and photographed. For the invasion assay, 100 µL of 200 µg/mL Matrigel (Corning, USA) was added, and the cells were seeded after incubation at 37 ℃ for 1 hour ( 11 ). Transwell chambers required no additional treatment for the migration assays.…”

The role of RNA methyltransferase METTL3 in gynecologic cancers: Results and mechanisms

“…It has been demonstrated that PLAA induces Mettl3 degradation by elevating the level of Mettl3 ubiquitination. Low levels of Mettl3 decreased the m6A methylation level of TRPC3 mRNA and inhibited TRPC3 expression, which resulted in lower intracellular calcium levels and suppressed OC cell metastasis ( Shen et al, 2022b ). Meanwhile, the Mettl3/YTHDF2 axis represses tumor suppressor gene IFFO1 expression and promotes mRNA degradation via an m6A methylation-dependent pathway, ultimately affecting the growth and development, metastasis and invasion, and cisplatin sensitivity of OC cells ( Zhang et al, 2023 ).…”