Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas.
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.
Department of Laboratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, 210029, China.|Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Hong
H
Yan
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.|School of Preclinical Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.
Lei
L
Bi
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.|International Biotechnology R&D Center, Shandong University School of Ocean, Weihai, Shandong, 264209, China.
Yunshan
Y
Wang
Department of Tuberculosis, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, 210029, China.
Xia
X
Zhang
Department of First Respiratory, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, 210029, China.
Zhibo
Z
Hou
Department of Laboratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, 210029, China.
Qian
Q
Wang
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Antoine M
AM
Snijders
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. JHMao@lbl.gov.
Jian-Hua
JH
Mao
D000230:Adenocarcinoma / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D044842:Cullin Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology*
C114234:CUL4A protein, human; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins