DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53.
Mutation in the TP53 gene positively correlates with increased incidence of chemoresistance in different cancers. In this study, we investigated the mechanism of chemoresistance and epithelial-to-mesenchymal transition (EMT) in colorectal cancer involving the gain-of-function (GOF) mutant p53/ephrin-B2 signaling axis. Bioinformatic analysis of the NCI-60 data set and subsequent hub prediction identified EFNB2 as a possible GOF mutant p53 target gene, responsible for chemoresistance. We show that the mutant p53-NF-Y complex transcriptionally upregulates EFNB2 expression in response to DNA damage. Moreover, the acetylated form of mutant p53 protein is recruited on the EFNB2 promoter and positively regulates its expression in conjunction with coactivator p300. In vitro cell line and in vivo nude mice data show that EFNB2 silencing restores chemosensitivity in mutant p53-harboring tumors. In addition, we observed high expression of EFNB2 in patients having neoadjuvant non-responder colorectal carcinoma compared with those having responder version of the disease. In the course of deciphering the drug resistance mechanism, we also show that ephrin-B2 reverse signaling induces ABCG2 expression after drug treatment that involves JNK-c-Jun signaling in mutant p53 cells. Moreover, 5-fluorouracil-induced ephrin-B2 reverse signaling promotes tumorigenesis through the Src-ERK pathway, and drives EMT via the Src-FAK pathway. We thus conclude that targeting ephrin-B2 might enhance the therapeutic potential of DNA-damaging chemotherapeutic agents in mutant p53-bearing human tumors.
Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
S K
SK
Alam
G.N.R. Knowledge Centre for Genome Informatics, Proteomics and Structural Biology Unit, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, India.
V K
VK
Yadav
Advanced Molecular Diagnostics Laboratory, Princess Margaret Hospital/The Ontario Cancer Institute, Toronto, ON, Canada.
S
S
Bajaj
Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
A
A
Datta
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
S K
SK
Dutta
Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
M
M
Bhattacharyya
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
S
S
Bhattacharya
Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
S
S
Debnath
Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
S
S
Roy
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.
L A
LA
Boardman
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
T C
TC
Smyrk
Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
J R
JR
Molina
Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
S
S
Chakrabarti
G.N.R. Knowledge Centre for Genome Informatics, Proteomics and Structural Biology Unit, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, India.|Structural Biology Unit, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, India.
S
S
Chowdhury
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
D
D
Mukhopadhyay
Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
S
S
Roychoudhury
D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C000601239:EFNB2 protein, human; D036388:Ephrin-B2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53