| Triple-negative breast cancer(TNBC)is an aggressive breast cancer which shows high metastatic capability and poor prognosis.In order to specifically and effectively kill cancer cells by therapies that induce DNA damage,it is important to take advantage of specific abnormalities in the DNA damage response machinery that are present in cancer cells but not in normal cells.Such properties of cancer cells can provide biomarkers or targets for sensitization.FoxO transcription factors have been reported to play pivotal roles in tumorigenesis.However,little is known about how FoxO specifically modulate DNA damage and repair.Here,we demonstrated that the interplay between FoxO and epigenetic factor HMD can regulate DNA damage repair.FoxO depletion decreased expression of homologous recombination repair-related protein(HR-X)in TNBC cells.In addition,we identified an epigenetic modifier-HMD which can interact with FoxO.We found that HMD depletion resulted in HR-X down-regulation in TNBC cells.However,FoxO depletion failed to futher induce HR-X in the absence of HMD,suggesting that HMD and FoxO act in the same pathway to regulate HR-X expression.We further demonstrated that FoxO can directly regulate transcription of HR-X.Meanwhile,we identified FoxO can directly interact with HMD.However,the detailed molecular mechanism as how HMD may cooperate with FoxO to regulate HR-X is still unknown.We have two hypotheses here.One is that HMD may directly modulate FoxO post-transcriptional modification,therefore influence the transcriptional activity of FoxO.Two is that HMD may directly acts on the promoter of HR-X while binding with FoxO,therefore HMD may modulate histone of HR-X promoter.We found that TNBC cells are more sensitive to PARP inhibitor treatment upon depletion of FoxO or HMD.Our findings suggest targeting HMD/FoxO-mediated HR-X expression may sensitize TNBC cells to PARP inhibitor treatment.The detail molecular mechanism needs further investigation. |
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