Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas
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. In conclusion, our results suggest that different CUL4-DCAF axis plays the distinct roles in LuADC development with possible relevance for therapeutic targetmore »
- Authors:
-
- Nanjing Chest Hospital, Nanjing (China). Dept. of Lab. Medicine; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Nanjing University of Chinese Medicine, Nanjing (China). School of Preclinical Medicine
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Shandong Univ. School of Ocean, Weihai, Shandong (China). International Biotechnology R&D Center
- Nanjing Chest Hospital, Nanjing (China). Dept. of Tuberculosis
- Nanjing Chest Hospital, Nanjing (China). Dept. of First Respiratory
- Nanjing Chest Hospital, Nanjing (China). Dept. of Lab. Medicine
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Natural Science Foundation of China (NSFC)
- OSTI Identifier:
- 1408492
- Grant/Contract Number:
- AC02-05CH11231; R01 CA116481; 81273638; 81503486; 81402193; 81500029
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 7; Journal Issue: 1; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
Citation Formats
Yan, Hong, Bi, Lei, Wang, Yunshan, Zhang, Xia, Hou, Zhibo, Wang, Qian, Snijders, Antoine M., and Mao, Jian-Hua. Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas. United States: N. p., 2017.
Web. doi:10.1038/s41598-017-00512-1.
Yan, Hong, Bi, Lei, Wang, Yunshan, Zhang, Xia, Hou, Zhibo, Wang, Qian, Snijders, Antoine M., & Mao, Jian-Hua. Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas. United States. https://doi.org/10.1038/s41598-017-00512-1
Yan, Hong, Bi, Lei, Wang, Yunshan, Zhang, Xia, Hou, Zhibo, Wang, Qian, Snijders, Antoine M., and Mao, Jian-Hua. Thu .
"Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas". United States. https://doi.org/10.1038/s41598-017-00512-1. https://www.osti.gov/servlets/purl/1408492.
@article{osti_1408492,
title = {Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas},
author = {Yan, Hong and Bi, Lei and Wang, Yunshan and Zhang, Xia and Hou, Zhibo and Wang, Qian and Snijders, Antoine M. and Mao, Jian-Hua},
abstractNote = {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. In conclusion, our results suggest that different CUL4-DCAF axis plays the distinct roles in LuADC development with possible relevance for therapeutic target development.},
doi = {10.1038/s41598-017-00512-1},
journal = {Scientific Reports},
number = 1,
volume = 7,
place = {United States},
year = {Thu Mar 23 00:00:00 EDT 2017},
month = {Thu Mar 23 00:00:00 EDT 2017}
}
Web of Science
Works referenced in this record:
Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib
journal, May 2004
- Lynch, Thomas J.; Bell, Daphne W.; Sordella, Raffaella
- New England Journal of Medicine, Vol. 350, Issue 21
The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data: Figure 1.
journal, May 2012
- Cerami, Ethan; Gao, Jianjiong; Dogrusoz, Ugur
- Cancer Discovery, Vol. 2, Issue 5
Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
journal, March 2013
- Gao, J.; Aksoy, B. A.; Dogrusoz, U.
- Science Signaling, Vol. 6, Issue 269
Cullin Family Proteins and Tumorigenesis: Genetic Association and Molecular Mechanisms
journal, January 2015
- Chen, Zhi; Sui, Jie; Zhang, Fan
- Journal of Cancer, Vol. 6, Issue 3
Targeting the ubiquitin–proteasome pathway with inorganic compounds to fight cancer: a challenge for the future
journal, March 2012
- Dalla Via, Lisa; Nardon, Chiara; Fregona, Dolores
- Future Medicinal Chemistry, Vol. 4, Issue 4
Identification of retinoic acid-regulated nuclear matrix-associated protein as a novel regulator of gastric cancer
journal, August 2009
- Li, J.; Ng, E. K. O.; Ng, Y. P.
- British Journal of Cancer, Vol. 101, Issue 4
Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes
journal, December 2009
- Melchor, Lorenzo; Saucedo-Cuevas, Laura Paula; Muñoz-Repeto, Iván
- Breast Cancer Research, Vol. 11, Issue 6
Lung tumourigenesis in a conditional Cul4A transgenic mouse model : Cul4A in lung tumourigenesis
journal, May 2014
- Yang, Yi-Lin; Hung, Ming-Szu; Wang, Yang
- The Journal of Pathology, Vol. 233, Issue 2
WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013
journal, May 2013
- Wang, Jing; Duncan, Dexter; Shi, Zhiao
- Nucleic Acids Research, Vol. 41, Issue W1
Human homologue for Caenorhabditis elegans CUL-4 protein overexpression is associated with malignant potential of epithelial ovarian tumours and poor outcome in carcinoma
journal, March 2012
- Birner, Peter; Schoppmann, Alexandra; Schindl, Monika
- Journal of Clinical Pathology, Vol. 65, Issue 6
Cancer statistics, 2016: Cancer Statistics, 2016
journal, January 2016
- Siegel, Rebecca L.; Miller, Kimberly D.; Jemal, Ahmedin
- CA: A Cancer Journal for Clinicians, Vol. 66, Issue 1
CUL4–DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation
journal, October 2006
- Higa, Leigh Ann; Wu, Min; Ye, Tao
- Nature Cell Biology, Vol. 8, Issue 11
Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma
journal, August 2016
- Benamar, Mouadh; Guessous, Fadila; Du, Kangping
- EBioMedicine, Vol. 10
Roles of ubiquitin signaling in transcription regulation
journal, February 2012
- Hammond-Martel, Ian; Yu, Helen; Affar, El Bachir
- Cellular Signalling, Vol. 24, Issue 2
Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain
journal, February 2005
- Pao, William; Miller, Vincent A.; Politi, Katerina A.
- PLoS Medicine, Vol. 2, Issue 3
TFDP1, CUL4A, andCDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas
journal, June 2002
- Yasui, Kohichiroh; Arii, Shigeki; Zhao, Chen
- Hepatology, Vol. 35, Issue 6
Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery
journal, October 2006
- Angers, Stephane; Li, Ti; Yi, Xianhua
- Nature, Vol. 443, Issue 7111
Cul4A is an oncogene in malignant pleural mesothelioma
journal, February 2011
- Hung, Ming-Szu; Mao, Jian-Hua; Xu, Zhidong
- Journal of Cellular and Molecular Medicine, Vol. 15, Issue 2
CUL4A Abrogation Augments DNA Damage Response and Protection against Skin Carcinogenesis
journal, May 2009
- Liu, Liren; Lee, Sharrell; Zhang, Jianxuan
- Molecular Cell, Vol. 34, Issue 4
The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase
journal, June 2014
- Olivero, Martina; Dettori, Daniela; Arena, Sabrina
- Oncotarget, Vol. 5, Issue 15
CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR
journal, January 2014
- Wang, Yunshan; Zhang, Pengju; Liu, Ziming
- Molecular Cancer, Vol. 13, Issue 1
Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer
journal, March 2012
- Ren, Shancheng; Xu, Chuanliang; Cui, Zilian
- Journal of Molecular Medicine, Vol. 90, Issue 10
1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma
journal, August 2011
- Mackintosh, C.; Ordóñez, J. L.; García-Domínguez, D. J.
- Oncogene, Vol. 31, Issue 10
WebGestalt: an integrated system for exploring gene sets in various biological contexts
journal, July 2005
- Zhang, B.; Kirov, S.; Snoddy, J.
- Nucleic Acids Research, Vol. 33, Issue Web Server
Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus
journal, February 2010
- Li, Wei; You, Liru; Cooper, Jonathan
- Cell, Vol. 140, Issue 4
Deubiquitinases in cancer: new functions and therapeutic options
journal, September 2011
- Fraile, J. M.; Quesada, V.; Rodríguez, D.
- Oncogene, Vol. 31, Issue 19
Cancer treatment and survivorship statistics, 2016
journal, June 2016
- Miller, Kimberly D.; Siegel, Rebecca L.; Lin, Chun Chieh
- CA: A Cancer Journal for Clinicians, Vol. 66, Issue 4
DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint
journal, November 2006
- Sansam, C. L.; Shepard, J. L.; Lai, K.
- Genes & Development, Vol. 20, Issue 22
Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients
journal, June 2016
- Szász, A. Marcell; Lánczky, András; Nagy, Ádám
- Oncotarget, Vol. 7, Issue 31
Glycolysis reprogramming in cancer-associated fibroblasts promotes the growth of oral cancer through the lncRNA H19/miR-675-5p/PFKFB3 signaling pathway
journal, March 2021
- Yang, Jin; Shi, Xueke; Yang, Miao
- International Journal of Oral Science, Vol. 13, Issue 1
A genomic and epigenomic atlas of prostate cancer in Asian populations
journal, March 2020
- Li, Jing; Xu, Chuanliang; Lee, Hyung Joo
- Nature, Vol. 580, Issue 7801
Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus
journal, February 2010
- Li, Wei; You, Liru; Cooper, Jonathan
- Cell, Vol. 140, Issue 4
CUL4A Abrogation Augments DNA Damage Response and Protection against Skin Carcinogenesis
journal, May 2009
- Liu, Liren; Lee, Sharrell; Zhang, Jianxuan
- Molecular Cell, Vol. 34, Issue 4
Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery
journal, October 2006
- Angers, Stephane; Li, Ti; Yi, Xianhua
- Nature, Vol. 443, Issue 7111
CUL4–DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation
journal, October 2006
- Higa, Leigh Ann; Wu, Min; Ye, Tao
- Nature Cell Biology, Vol. 8, Issue 11
1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma
journal, August 2011
- Mackintosh, C.; Ordóñez, J. L.; García-Domínguez, D. J.
- Oncogene, Vol. 31, Issue 10
Deubiquitinases in cancer: new functions and therapeutic options
journal, September 2011
- Fraile, J. M.; Quesada, V.; Rodríguez, D.
- Oncogene, Vol. 31, Issue 19
Genetic and epigenetic regulation of the NRF2-KEAP1 pathway in human lung cancer
journal, November 2021
- Camiña, Nuria; Penning, Trevor M.
- British Journal of Cancer, Vol. 126, Issue 9
TFDP1, CUL4A, andCDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas
journal, June 2002
- Yasui, Kohichiroh; Arii, Shigeki; Zhao, Chen
- Hepatology, Vol. 35, Issue 6
Targeting Targeted Therapy
journal, May 2004
- Green, Mark R.
- New England Journal of Medicine, Vol. 350, Issue 21
Ubiquitin E3 Ligase CRL4 CDT2/DCAF2 as a Potential Chemotherapeutic Target for Ovarian Surface Epithelial Cancer
journal, August 2013
- Pan, Wei-Wei; Zhou, Jian-Jie; Yu, Chao
- Journal of Biological Chemistry, Vol. 288, Issue 41
WebGestalt: an integrated system for exploring gene sets in various biological contexts
journal, July 2005
- Zhang, B.; Kirov, S.; Snoddy, J.
- Nucleic Acids Research, Vol. 33, Issue Web Server
WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013
journal, May 2013
- Wang, Jing; Duncan, Dexter; Shi, Zhiao
- Nucleic Acids Research, Vol. 41, Issue W1
DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint
journal, November 2006
- Sansam, C. L.; Shepard, J. L.; Lai, K.
- Genes & Development, Vol. 20, Issue 22
Cul4A is an oncogene in malignant pleural mesothelioma
journal, February 2011
- Hung, Ming-Szu; Mao, Jian-Hua; Xu, Zhidong
- Journal of Cellular and Molecular Medicine, Vol. 15, Issue 2
CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR
journal, January 2014
- Wang, Yunshan; Zhang, Pengju; Liu, Ziming
- Molecular Cancer, Vol. 13, Issue 1
Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes
journal, December 2009
- Melchor, Lorenzo; Saucedo-Cuevas, Laura Paula; Muñoz-Repeto, Iván
- Breast Cancer Research, Vol. 11, Issue 6
Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain
journal, February 2005
- Pao, William; Miller, Vincent A.; Politi, Katerina A.
- PLoS Medicine, Vol. 2, Issue 3
Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic
journal, December 2014
- Abidi, Naima; Xirodimas, Dimitris P.
- Endocrine-Related Cancer, Vol. 22, Issue 1
The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase
journal, June 2014
- Olivero, Martina; Dettori, Daniela; Arena, Sabrina
- Oncotarget, Vol. 5, Issue 15
Cancer treatment and survivorship statistics, 2016
journal, June 2016
- Miller, Kimberly D.; Siegel, Rebecca L.; Lin, Chun Chieh
- CA: A Cancer Journal for Clinicians, Vol. 66, Issue 4
Targeting the ubiquitin–proteasome pathway with inorganic compounds to fight cancer: a challenge for the future
journal, March 2012
- Dalla Via, Lisa; Nardon, Chiara; Fregona, Dolores
- Future Medicinal Chemistry, Vol. 4, Issue 4
Works referencing / citing this record:
Gene-based evaluation of low-frequency variation and genetically-predicted gene expression impacting risk of keloid formation
journal, February 2018
- Hellwege, Jacklyn N.; Russell, Shirley B.; Williams, Scott M.
- Annals of Human Genetics, Vol. 82, Issue 4
Joint Transcriptomic Analysis of Lung Cancer and Other Lung Diseases
journal, December 2019
- Otálora-Otálora, Beatriz Andrea; Florez, Mauro; López-Kleine, Liliana
- Frontiers in Genetics, Vol. 10
Integrated analysis reveals five potential ceRNA biomarkers in human lung adenocarcinoma
journal, April 2019
- Liu, Yu; Xie, Deyao; He, Zhifeng
- PeerJ, Vol. 7