PLAAT2 suppresses gastric cancer progression by facilitating cMyc ubiquitination and inhibiting MEK/ERK signaling.

Gastric cancer (GC) is a significant global public health issue due to its high incidence and limited therapeutic options. This study aimed to explore the role of phospholipase A and acyltransferase 2 (PLAAT2) in GC progression and its molecular mechanisms. A total of 116 pairs of GC and adjacent tissues, along with 116 paraffin-embedded GC tissue sections, were collected from the Cancer Hospital of China Medical University. The expression of PLAAT2 in GC tissues and cells was detected using quantitative reverse transcription-polymerase chain reaction and western blot assays. Its effects on proliferation, migration, invasion, and apoptosis were assessed using functional assays. The impact on mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway and EMT-related proteins was examined through western blot. Immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation (co-IP), and ubiquitination assays were conducted to elucidate the molecular mechanisms of PLAAT2 to identify PLAAT2-interacting proteins, particularly its role in cMyc posttranslational regulation. In vivo xenograft models further validated the tumor-suppressive role of PLAAT2. We identified PLAAT2 as a differentially expressed gene associated with prognosis in the datasets of patients with GC. PLAAT2 was downregulated in GC and correlated with poor prognosis. Functional experiments demonstrated that PLAAT2 inhibited GC cell proliferation, migration, and invasion through the MEK/ERK signaling pathway. IP-MS and co-IP revealed that cMyc and tripartite motif containing 32 (TRIM32) were key PLAAT2-binding partners. PLAAT2 facilitated the recruitment of TRIM32 to promote cMyc ubiquitination and degradation, thereby suppressing the MEK/ERK signaling pathway and reducing oncogenic potential in vitro and in vivo. PLAAT2 functions as a tumor suppressor in GC by recruiting TRIM32 to facilitate cMyc ubiquitination and impair MEK/ERK-driven oncogenic signaling, highlighting the PLAAT2/TRIM32/cMyc axis as a potential therapeutic target.