PADI2‐Catalyzed MEK1 Citrullination Activates ERK1/2 and Promotes IGF2BP1‐Mediated SOX2 mRNA Stability in Endometrial Cancer

Abstract

Peptidylarginine deiminase II (PADI2) converts positively charged arginine residues to neutrally charged citrulline, and this activity has been associated with the onset and progression of multiple cancers. However, a role for PADI2 in endometrial cancer (EC) has not been previously explored. This study demonstrates that PADI2 is positively associated with EC proregression. Mechanistically, PADI2 interacting and catalyzing MEK1 citrullination at arginine 113/189 facilitates MEK1 on extracellular signal‐regulated protein kinases 1/2 (ERK1/2) phosphorylation, which activates insulin‐like growth factor‐II binding protein 1 (IGF2BP1) expression. Furthermore, RNA immunoprecipitation (RIP) and RNA stability analyses reveal that IGF2BP1 binds to the m6A sites in SOX2‐3′UTR to prevent SOX2 mRNA degradation. Dysregulation of IGF2BP1 by PADI2/MEK1/ERK signaling results in abnormal accumulation of oncogenic SOX2 expression, therefore supporting the malignant state of EC. Finally, PADI2 gene silencing, inhibiting MEK1 citrullination by PADI2 inhibitor, or mutation of MEK1 R113/189 equally inhibits EC progression. These data demonstrate that PADI2‐catalyzed MEK1 R113/189 citrullination is a critical diver for EC malignancies and suggest that targeting PADI2/MEK1 can be a potential therapeutic approach in patients with EC.

Functions, mechanisms, and therapeutic implications of METTL14 in human cancer

“…Endometrial cancer (EC) is a common malignant gynecological tumor worldwide. Even in early-stage cancer, routine surgery has a great impact on the fertility of patients, and the development of effective interventions is of great importance [ 99 , 100 ]. Ma et al reported that m 6 A RNA methylation was closely associated with the clinicopathological stage and prognosis of endometrial cancer and that METTL14 was used as a potential marker for the diagnosis and prognosis of endometrial cancer [ 101 ].…”

m6A hypomethylation of DNMT3B regulated by ALKBH5 promotes intervertebral disc degeneration via E4F1 deficiency

“…Among over 100 types of RNA modifications, m6A is the most prevalent one in modification of mRNA and non‐coding RNA 45 . Accumulating evidences indicate that m6A is involved in a series of physical and pathological processes, including embryonic stem cells development, tumorigenesis, spermatogonia differentiation, CNS myelination, heart failure and diabetes 46–54 . Recent studies revealed that demethylase FTO could control cell cycle progression and proliferation by targeting m6A modification of cyclin D1 mRNA 32 .…”

“… 45 Accumulating evidences indicate that m6A is involved in a series of physical and pathological processes, including embryonic stem cells development, tumorigenesis, spermatogonia differentiation, CNS myelination, heart failure and diabetes. 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 Recent studies revealed that demethylase FTO could control cell cycle progression and proliferation by targeting m6A modification of cyclin D1 mRNA. 32 What's more, expression of miRNA in cellular aging of HDFs and old PBMCs could be regulated by m6A‐dependent AGO2 expression.…”

Emerging Roles of m6A RNA Methylation Regulators in Gynecological Cancer

“…PADI2-catalyzed MEK1 R113/189 citrulline is a key factor in endometrial cancer. These findings suggest that targeting PADI2/MEK1 may be a potential therapy for endometrial cancer patients (91). The roles of different m 6 A regulators in regulating RNAs in endometrial cancer are shown in Figure 3 and Table 2.…”