PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cancer driver gene identification is crucial for understanding tumor biology and developing targeted therapies.
• Mechanisms of less common mutations in cancer development require further investigation.
• This study focuses on the novel driver PARP4 using the largest Asian lung adenocarcinoma (LUAD) cohort.

Purpose of the Study:

• To functionally assess the mechanistic role of PARP4 in lung adenocarcinoma.
• To investigate PARP4's interaction partners and their role in tumorigenesis.
• To explore the link between PARP4, splicing alterations, and LUAD development.

Main Methods:

• In vitro and in vivo tumorigenicity assays were performed to evaluate the effects of PARP4 loss and mutation.
• Interactomics analysis using quantitative mass spectrometry identified PARP4 interaction partners.
• Transcriptomic data from cell lines and patient tumors were analyzed to investigate splicing alterations.

Main Results:

• PARP4 depletion or mutation (I1039T) enhanced the tumorigenicity of KRAS- or EGFR-driven lung cancer cells.
• PARP4's tumor suppressive activity is independent of the vault complex.
• The splicing regulator hnRNPM was identified as a novel PARP4 interaction partner; its loss also promoted tumor formation and led to splicing perturbations, similar to PARP4 knockdown and LUAD patients with PARP4 copy number loss.

Conclusions:

• PARP4 is a novel tumor suppressor in lung adenocarcinoma.
• PARP4's tumor suppressive activity is mediated through its interaction with hnRNPM, not the vault complex.
• Splicing dysregulation, influenced by PARP4 and hnRNPM, plays a significant role in LUAD tumorigenesis.