Histone Code Modulation by Oncogenic PWWP-Domain Protein in Breast Cancers
Final rept. 1 Jun 2009-31 May 2014
WAYNE STATE UNIV DETROIT MI
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Amplification of 8p11-12 occurs in approximately 15 of human breast cancer HBC, and this region of amplification is significantly associated with disease-specific survival and distant recurrence in breast cancer patients. Earlier, we identified Wolf-Hirschhorn syndrome candidate 1-like 1 WHSC1L1 as a candidate oncogene of 8p11-12 amplified region, based on statistical analysis of copy number increase and overexpression. In this study, we demonstrated that WHSC1L1 acts as a transforming gene stable WHSC1L1 overexpression in nontumorigenic MCF10A cells induces transformed phenotypes, whereas WHSC1L1 knockdown in 8p12 amplified, ER-positive breast cancer cells inhibits proliferation in vitro. We also found that overexpression of WHSC1L1 likely induces the acquisition of stem cell-like properties in vitro. WHSC1L1 family proteins have been shown to bind to methylated histones, specifically H3K36 methylation marks. We determined global methylation levels in a panel of breast cancer cell lines, including WHSC1L1-amplified SUM-44 and SUM-52 lines. We identified several WHSC1L1 target genes, one of which is the Iroquois homeobox 3 gene, a member of the Iroquois homeobox transcription factor family. In summary, our findings provide a strong foundation for further mechanistic research and therapeutic options using WHSC1L inhibitors to treat breast cancer.
- Medicine and Medical Research