PMID- 28733611
OWN - NLM
STAT- MEDLINE
DCOM- 20190225
LR  - 20190225
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Jul 21
TI  - Integrin alpha6beta4 Upregulates Amphiregulin and Epiregulin through Base Excision 
      Repair-Mediated DNA Demethylation and Promotes Genome-wide DNA Hypomethylation.
PG  - 6174
LID - 10.1038/s41598-017-06351-4 [doi]
LID - 6174
AB  - Aberrant DNA methylation patterns are a common theme across all cancer types. 
      Specific DNA demethylation of regulatory sequences can result in upregulation of 
      genes that are critical for tumor development and progression. Integrin alpha6beta4 is 
      highly expressed in pancreatic carcinoma and contributes to cancer progression, 
      in part, through the specific DNA demethylation and upregulation of epidermal 
      growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG). 
      Whole genome bisulfite sequencing (WGBS) revealed that integrin alpha6beta4 signaling 
      promotes an overall hypomethylated state and site specific DNA demethylation of 
      enhancer elements within the proximal promoters of AREG and EREG. Additionally, 
      we find that the base excision repair (BER) pathway is required to maintain 
      expression of AREG and EREG, as blocking DNA repair molecules, TET1 GADD45A, TDG, 
      or PARP-1 decreased gene expression. Likewise, we provide the novel finding that 
      integrin alpha6beta4 confers an enhanced ability on cells to repair DNA lesions and 
      survive insult. Therefore, while many known signaling functions mediated by 
      integrin alpha6beta4 that promote invasive properties have been established, this study 
      demonstrates that integrin alpha6beta4 can dramatically impact the epigenome of cancer 
      cells, direct global DNA methylation levels toward a hypomethylated state, and 
      impact DNA repair and subsequent cell survival.
FAU - Carpenter, Brittany L
AU  - Carpenter BL
AD  - Markey Cancer Center, University of Kentucky, Lexington, 40506-0509, USA.
AD  - Department of Molecular and Cellular Biochemistry, University of Kentucky, 
      Lexington, 40506-0509, USA.
FAU - Liu, Jinpeng
AU  - Liu J
AD  - Markey Cancer Center, University of Kentucky, Lexington, 40506-0509, USA.
FAU - Qi, Lei
AU  - Qi L
AD  - Markey Cancer Center, University of Kentucky, Lexington, 40506-0509, USA.
AD  - Department of Molecular and Cellular Biochemistry, University of Kentucky, 
      Lexington, 40506-0509, USA.
FAU - Wang, Chi
AU  - Wang C
AD  - Markey Cancer Center, University of Kentucky, Lexington, 40506-0509, USA.
AD  - Department of Biostatistics, Division of Cancer Biostatistics, University of 
      Kentucky, Lexington, 40506-0509, USA.
FAU - O'Connor, Kathleen L
AU  - O'Connor KL
AD  - Markey Cancer Center, University of Kentucky, Lexington, 40506-0509, USA. 
      kloconnor@uky.edu.
AD  - Department of Molecular and Cellular Biochemistry, University of Kentucky, 
      Lexington, 40506-0509, USA. kloconnor@uky.edu.
LA  - eng
GR  - P30 CA177558/CA/NCI NIH HHS/United States
GR  - R21 CA178753/CA/NCI NIH HHS/United States
GR  - T32 CA165990/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170721
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (EREG protein, human)
RN  - 0 (Epiregulin)
RN  - 0 (Integrin alpha6beta4)
SB  - IM
MH  - Amphiregulin/*genetics
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - DNA Methylation
MH  - DNA Repair
MH  - Enhancer Elements, Genetic
MH  - Epigenesis, Genetic
MH  - Epiregulin/*genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Integrin alpha6beta4/*metabolism
MH  - Pancreatic Neoplasms/genetics/*metabolism
MH  - *Up-Regulation
MH  - Whole Genome Sequencing
PMC - PMC5522472
COIS- The authors declare that they have no competing interests.
EDAT- 2017/07/25 06:00
MHDA- 2019/02/26 06:00
PMCR- 2017/07/21
CRDT- 2017/07/23 06:00
PHST- 2017/01/03 00:00 [received]
PHST- 2017/06/13 00:00 [accepted]
PHST- 2017/07/23 06:00 [entrez]
PHST- 2017/07/25 06:00 [pubmed]
PHST- 2019/02/26 06:00 [medline]
PHST- 2017/07/21 00:00 [pmc-release]
AID - 10.1038/s41598-017-06351-4 [pii]
AID - 6351 [pii]
AID - 10.1038/s41598-017-06351-4 [doi]
PST - epublish
SO  - Sci Rep. 2017 Jul 21;7(1):6174. doi: 10.1038/s41598-017-06351-4.