CEBP?/miR-296-5p/PES1 Axis Regulates Cell Senescence

For most mammalians,somatic cells reaching their limitation of proliferation will lead to cell aging.Morphological enlargement and flattening of cell,enlargement of nucleus,irreversible cell cycle arrest,and cells secreting aging-related functional factors that change cell microenvironment to enhance cell aging are all characteristics of aging.If not being eliminated,both the activation of oncogenes and inactivation of tumor suppressors can cause abnormal cell proliferation and even cancer.However,the process of aging makes aging cell easier to be identified,from which we could tell that aging is a protective mechanism for organisms.In this case aging can be seen as a defense mechanism towards tumorigenesis,so the aging of cancer cells should lead to apoptosis or their elimination and thus cancer will be cured.During our study on PES1,a regulatory protein in estrogen signaling,we found that knockdown of this highly-expressed gene in cancer cells can prominently suppress the growth of cancer cells.In addition,change of cell morphology was also found in these cells.According to our results,PES1 knockdown cells became larger and flatter and nuclei were enlarged compared with normal cancer cells.These effects coincide with the morphological characteristics of cell aging.Next,more experiments were done to identify the mechanism of PES1 regulation of cell aging.We then found that PES1 suppresses the expression of p53,which plays an important role in cell cycle arrest and cell aging.We thus propose that PES1 may regulate cancer cell aging through p53.Next,we determined micorRNAs regulating PES1.We found that miR-296-5p can regulate both PES1 and cell aging.Thus,we detected whether miR-296-5p regulates cell aging through PES1.Given the observation of miR-296-5p's regulation on cell aging in PES1 knockdown cells,we concluded that miR-296-5p modulates cell agingdepending,at least in part,on PES1.We noticed that PES1 knockdown greatly attenuated the ability of miR-296-5p to induce sensecence.Bioinformatics analysis predicted that miR-296-5p promoter contained the binding site of CEBP?/?transcription factor.Indeed,both CEBP ? and ? increased miR-296-5p expression.However,CEBP ?,but not CEBP?,inhibited PES1 expression.Thus,we tested whether the CEBP?/miR-296-5p/PES1 pathway is relevant to aging.This hypothesis was verified in tumor clinical specimens.We analyzed the correlation between CEBP?/miR-296-5p/PES1 and aging in tissues from mice of different ages and also in collected breast cancer tissue samples and found that CEBP? and miR-296-5p are positively correlated with aging,and PES1 is negatively correlated with aging.In mice tissues,with age growing,the ratio of senescent cells is increased,miR-296-5p is inclined to go up,and the expression level of PES1 is reduced.These are in agreement with our results of experiments in vitro,suggesting that The CEBP?/miR-296-5p/PES1 regulation of cell aging is of physiological and pathological importance.In conclusion,we show for the first time a PES1-centered pathway regulating aging through p53,which is of both physiological and pathological significance.Our study not only elucidates new mechanism underlying cancer cell senescence but also provides a candidate for cancer therapy in terms of senescence.