TY - JOUR
T1 - A novel histone deacetylase inhibitor, Scriptaid, enhances expression of functional estrogen receptor α (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine
AU - Keen, Judith Clancy
AU - Yan, Lan
AU - Mack, Kelly M.
AU - Pettit, Catherine
AU - Smith, Dawn
AU - Sharma, Dipali
AU - Davidson, Nancy E.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health, CA 78352, CA88843 and CA09110.
PY - 2003/10
Y1 - 2003/10
N2 - Epigenetic mechanisms, such as DNA methylation and histone deacetylation, may play a role in loss of estrogen receptor α (ER) expression in ER negative human breast cancer cells. Our previous studies showed that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), resulted in expression of functional ER mRNA and protein. Therefore, we sought to characterize the effects of a recently described HDAC inhibitor, Scriptaid, on cell growth and ER expression and function in ER negative human breast cancer cell lines. Scriptaid treatment of three ER negative cell lines, MDA-MB-231, MDA-MB-435 and Hs578t, resulted in significant growth inhibition and increased acetylation of H3 and H4 histone tails. Quantitative Real Time PCR showed 2000-20,000-fold increase of ER mRNA transcript in all three cell lines after 48 h of Scriptaid treatment. Further, dose dependent re-expression of an estrogen responsive gene, the progesterone receptor (PR), indicated that induced ER is functional. As seen with TSA and AZA, Scriptaid and AZA co-treatment was more effective in inducing ER than Scriptaid or AZA alone. In vivo analysis using a xenograft mouse model bearing MDA-MB-231 tumors showed decreased tumor growth following Scriptaid or TSA treatment. Our results indicate that the novel HDAC inhibitor, Scriptaid, inhibits tumor growth in vitro and in vivo and, in conjunction with AZA, acts to re-express functional ER. These data suggest that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.
AB - Epigenetic mechanisms, such as DNA methylation and histone deacetylation, may play a role in loss of estrogen receptor α (ER) expression in ER negative human breast cancer cells. Our previous studies showed that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), resulted in expression of functional ER mRNA and protein. Therefore, we sought to characterize the effects of a recently described HDAC inhibitor, Scriptaid, on cell growth and ER expression and function in ER negative human breast cancer cell lines. Scriptaid treatment of three ER negative cell lines, MDA-MB-231, MDA-MB-435 and Hs578t, resulted in significant growth inhibition and increased acetylation of H3 and H4 histone tails. Quantitative Real Time PCR showed 2000-20,000-fold increase of ER mRNA transcript in all three cell lines after 48 h of Scriptaid treatment. Further, dose dependent re-expression of an estrogen responsive gene, the progesterone receptor (PR), indicated that induced ER is functional. As seen with TSA and AZA, Scriptaid and AZA co-treatment was more effective in inducing ER than Scriptaid or AZA alone. In vivo analysis using a xenograft mouse model bearing MDA-MB-231 tumors showed decreased tumor growth following Scriptaid or TSA treatment. Our results indicate that the novel HDAC inhibitor, Scriptaid, inhibits tumor growth in vitro and in vivo and, in conjunction with AZA, acts to re-express functional ER. These data suggest that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.
KW - 5-aza-2′-deoxycytidine
KW - Breast cancer
KW - DNA methylation
KW - Estrogen receptor α
KW - Histone acetylation
KW - Scriptaid
UR - http://www.scopus.com/inward/record.url?scp=0242330341&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0242330341&partnerID=8YFLogxK
U2 - 10.1023/A:1026146524737
DO - 10.1023/A:1026146524737
M3 - Article
C2 - 14620913
AN - SCOPUS:0242330341
SN - 0167-6806
VL - 81
SP - 177
EP - 186
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -