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Published on: October 11, 2019
Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung
Hong Yan1,2, Lei Bi2,3, Yunshan Wang2,4
1Department of Laboratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, 210029, China.
Abstract:
Many DDB1-CUL4 associated factors (DCAFs) have been identified and serve as substrate receptors. Although the oncogenic role of CUL4A has been well established, specific DCAFs involved in cancer development remain largely unknown. Here we infer the potential impact of 19 well-defined DCAFs in human lung adenocarcinomas (LuADCs) using integrative omics analyses, and discover that mRNA levels of DTL, DCAF4, 12 and 13 are consistently elevated whereas VBRBP is reduced in LuADCs compared to normal lung tissues. The transcriptional levels of DCAFs are significantly correlated with their gene copy number variations. SKIP2, DTL, DCAF6, 7, 8, 13 and 17 are frequently gained whereas VPRBP, PHIP, DCAF10, 12 and 15 are frequently lost. We find that only transcriptional level of DTL is robustly, significantly and negatively correlated with overall survival across independent datasets. Moreover, DTL-correlated genes are enriched in cell cycle and DNA repair pathways. We also identified that the levels of 25 proteins were significantly associated with DTL overexpression in LuADCs, which include significant decreases in protein level of the tumor supressor genes such as PDCD4, NKX2-1 and PRKAA1. Our results suggest that different CUL4-DCAF axis plays the distinct roles in LuADC development with possible relevance for therapeutic target development.
Insights
Researchers investigated 19 DDB1-CUL4 associated factors (DCAFs) in lung adenocarcinoma (LuADC). Elevated DTL levels correlate with poor survival and impact cell cycle and DNA repair, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DDB1-CUL4 associated factors (DCAFs) act as substrate receptors, but their roles in cancer, particularly lung adenocarcinoma (LuADC), are largely unknown.
- CUL4A's oncogenic role is established, yet specific DCAFs contributing to cancer development require elucidation.
Purpose of the Study:
- To investigate the potential impact of 19 defined DCAFs in human lung adenocarcinomas (LuADCs).
- To identify specific DCAFs associated with LuADC development and patient survival.
Main Methods:
- Integrative omics analyses were employed to assess DCAF expression in LuADCs.
- Correlation analyses were performed between DCAF transcriptional levels, gene copy number variations, and patient overall survival.
Main Results:
- mRNA levels of DTL, DCAF4, DCAF12, and DCAF13 were elevated, while VBRBP was reduced in LuADCs.
- DTL's transcriptional level significantly and negatively correlated with overall survival, with DTL-correlated genes enriched in cell cycle and DNA repair pathways.
- DTL overexpression was associated with decreased protein levels of tumor suppressors like PDCD4, NKX2-1, and PRKAA1.
Conclusions:
- Different CUL4-DCAF axes play distinct roles in LuADC development.
- DTL emerges as a potential therapeutic target in lung adenocarcinoma due to its association with survival and key cellular pathways.
