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Development of vitamin D‐resistance in breast cancer cells through SLUG‐mediated coordinate repression of CYP2R1, CYP27B1 and VDR gene promoters
Author(s) -
Mittal Mukul Kumar,
Misra Smita,
Chaudhuri Gautam
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.927.2
Subject(s) - calcitriol receptor , slug , biology , promoter , trichostatin a , cancer research , vitamin d and neurology , endocrinology , gene , gene expression , histone , histone deacetylase , genetics
Metastatic breast and other cancers are often found to be refractory to vitamin D therapy. We report here that the metastasis modulator protein SLUG, which is often over‐expressed in metastatic breast cancer cells, coordinately represses the levels of CYP2R1, CYP27B1 and VDR proteins in the breast cancer cells to induce vitamin D‐resistance in these cells. SLUG inhibits CYP2R1, CYP27B1 and VDR gene promoter activities in these cells. ChIP assays revealed that SLUG is recruited at the CYP2R1, CYP27B1 and VDR gene promoters along with the co‐repressor CtBP1 and the effector HDAC1. Inhibition of HDAC1 activity by Trichostatin A increased acetyl histones H3 and H4 at the CYP2R1, CYP27B1 and VDR gene promoters and abolished the repressor activities of SLUG. Knockdown of SLUG in highly invasive MDA‐MB‐231 and BT549 cells increased their CYP2R1, CYP27B1 and VDR gene expression and decreased their resistance to VD3 in vitro . Our data establish that SLUG regulates vitamin D metabolism and contribute to the induction of VD3‐resistance in human breast cancer cells through the inhibition of CYP2R1, CYP27B1 and VDR gene promoters epigenetically through chromatin remodeling. Supported in part by the NIH grant 1U54RR026140‐01 to SM and DOD‐CDMRP IDEA Grant# BC050641 to GC.