Breast cancer-associated fibroblasts confer AKT1-mediated epigenetic silencing of Cystatin M in epithelial cells.
The interplay between histone modifications and promoter hypermethylation provides a causative explanation for epigenetic gene silencing in cancer. Less is known about the upstream initiators that direct this process. Here, we report that the Cystatin M (CST6) tumor suppressor gene is concurrently down-regulated with other loci in breast epithelial cells cocultured with cancer-associated fibroblasts (CAF). Promoter hypermethylation of CST6 is associated with aberrant AKT1 activation in epithelial cells, as well as the disabled INNP4B regulator resulting from the suppression by CAFs. Repressive chromatin, marked by trimethyl-H3K27 and dimethyl-H3K9, and de novo DNA methylation is established at the promoter. The findings suggest that microenvironmental stimuli are triggers in this epigenetic cascade, leading to the long-term silencing of CST6 in breast tumors. Our present findings implicate a causal mechanism defining how tumor stromal fibroblasts support neoplastic progression by manipulating the epigenome of mammary epithelial cells. The result also highlights the importance of direct cell-cell contact between epithelial cells and the surrounding fibroblasts that confer this epigenetic perturbation. Because this two-way interaction is anticipated, the described coculture system can be used to determine the effect of epithelial factors on fibroblasts in future studies.
Lin
Huey-Jen L
HJ
Division of Medical Technology, School of Allied Medical Professions, Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210, USA. huey-jen.lin@osumc.edu
Zuo
Tao
T
Lin
Ching-Hung
CH
Kuo
Chieh Ti
CT
Liyanarachchi
Sandya
S
Sun
Shuying
S
Shen
Rulong
R
Deatherage
Daniel E
DE
Potter
Dustin
D
Asamoto
Lisa
L
Lin
Shili
S
Yan
Pearlly S
PS
Cheng
Ann-Lii
AL
Ostrowski
Michael C
MC
Huang
Tim H-M
TH
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D002450:Cell Communication / Q000235:genetics; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D055332:Cystatin M / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
C525104:CST6 protein, human; D055332:Cystatin M; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt