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UBE3A and MCM6 synergistically regulate the proliferation and migration of lung adenocarcinoma cells
Yanyan Luo1,2, Yun Yang2,3, Cong Yang4
1Department of Pain, Wenzhou Key Laboratory of Perioperative Medicine, The First Affiliated Hospital of Wenzhou Medical University, China.
Abstract:
Lung cancer is a leading cause of mortality worldwide and shows substantial clinical and biomolecular heterogeneity. Currently, specific therapeutic strategies are lacking, so effective drug targets are urgently needed. E6AP/UBE3A is a multifaceted ubiquitin ligase that controls various signaling pathways implicated in neurological diseases and various cancers; however, its role in lung cancer is incompletely understood. Here, MCM6 was identified as an interacting partner of E6AP using the yeast two-hybrid assay. MCM2 and MCM4 were then shown to interact with E6AP. E6AP knockout enhanced the ubiquitination of MCM2/4/6, suggesting that E6AP was not the E3 ubiquitin ligase for these three MCM proteins. Ablation of E6AP inhibited proliferation and migration, but had no significant effect on apoptosis in A549 and H1975 cells, and proliferation and migration inhibition was also observed in MCM6 knockdown cells. Furthermore, ablation of MCM6 and E6AP synergistically suppressed the proliferation and migration of A549 and H1975 cells. To verify the above findings in vivo, we established tumor models in nude mice and identified that the tumorigenicity of human lung adenocarcinoma (LUAD) cells was synergistically regulated by MCM6 and E6AP. Moreover, the expression levels of MCM6 and E6AP were higher in LUAD tissues than in adjacent tissues. Furthermore, the expression levels of MCM6 and E6AP were positively correlated in human LUAD samples. Thus, our study suggests that the interaction of E6AP and MCM proteins plays an important role in the progression of LUAD, which might offer potential therapeutic targets for cancer treatment.
Insights
The E3 ubiquitin ligase E6AP (also known as UBE3A) and MCM proteins MCM2, MCM4, and MCM6 interact and play a crucial role in lung adenocarcinoma progression. Targeting this interaction may offer new therapeutic strategies for lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lung cancer is a major global health concern with significant heterogeneity, necessitating novel therapeutic targets.
- E3 ubiquitin ligase E6AP (UBE3A) is involved in various cancers, but its role in lung cancer remains unclear.
- The MCM (minichromosome maintenance) complex proteins are essential for DNA replication and have been implicated in cancer.
Purpose of the Study:
- To investigate the role of E3 ubiquitin ligase E6AP and its interaction with MCM proteins in lung adenocarcinoma (LUAD).
- To identify potential therapeutic targets for LUAD based on the E6AP-MCM interaction.
- To elucidate the functional consequences of E6AP and MCM6 interplay in LUAD cell proliferation, migration, and tumorigenicity.
Main Methods:
- Yeast two-hybrid assay to identify E6AP interacting partners.
- Co-immunoprecipitation to confirm interactions between E6AP and MCM2/4/6.
- Cell proliferation and migration assays (e.g., in A549 and H1975 cells) following E6AP or MCM6 knockdown/ablation.
- In vivo tumor xenograft models in nude mice to assess tumorigenicity.
- Analysis of E6AP and MCM6 expression levels in human LUAD tissues versus adjacent normal tissues.
Main Results:
- MCM6 was identified as an interacting partner of E6AP; MCM2 and MCM4 also interact with E6AP.
- Ablation of E6AP inhibited LUAD cell proliferation and migration, but not apoptosis.
- Knockdown of MCM6 also inhibited cell proliferation and migration.
- Combined ablation of E6AP and MCM6 synergistically suppressed LUAD cell proliferation and migration.
- E6AP and MCM6 expression levels were elevated in LUAD tissues and positively correlated.
- Tumorigenicity of LUAD cells was synergistically regulated by E6AP and MCM6 in vivo.
Conclusions:
- The interaction between E6AP and MCM proteins (MCM2/4/6) is critical for the progression of lung adenocarcinoma.
- E6AP and MCM6 act synergistically to promote LUAD cell proliferation, migration, and tumorigenicity.
- The E6AP-MCM protein interaction represents a promising therapeutic target for lung adenocarcinoma treatment.
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