Abstract
Cellular senescence is a tumor-suppressive mechanism blocking cell proliferation in response to stress. However, recent evidence suggests that senescent tumor cells can re-enter the cell cycle to become cancer stem cells, leading to relapse after cancer chemotherapy treatment. Understanding how the senescence reprogramming process is a precursor to cancer stem cell formation is of great medical importance. To study the interplay between senescence, stemness, and cancer, we applied a stem cell medium (SCM) to human embryonic fibroblasts (MRC5 and WI-38) and cancer cell lines (A549 and 293T). MRC5 and WI-38 cells treated with SCM showed symptoms of oxidative stress and became senescent. Transcriptome analysis over a time course of SCM-induced senescence, revealed a developmental process overlapping with the upregulation of genes for growth arrest and the senescence-associated secretory phenotype (SASP). We demonstrate that histone demethylases jumonji domain-containing protein D3 (Jmjd3) and ubiquitously transcribed tetratricopeptide repeat, X chromosome (Utx), which operate by remodeling chromatin structure, are implicated in the senescence reprogramming process to block stem cell formation in fibroblasts. In contrast, A549 and 293T cells cultured in SCM were converted to cancer stem cells that displayed the phenotype of senescence uncoupled from growth arrest. The direct overexpression of DNA methyltransferases (Dnmt1 and Dnmt3A), ten-eleven translocation methylcytosine dioxygenases (Tet1 and Tet3), Jmjd3, and Utx proteins could activate senescence-associated beta-galactosidase (SA-β-gal) activity in 293T cells, suggesting that epigenetic alteration and chromatin remodeling factors trigger the senescence response. Overall, our study suggests that chromatin machinery controlling senescence reprogramming is significant in cancer stem cell formation.
Highlights
Cellular senescence is a permanent cell proliferation arrest that is triggered by stress, which includes telomere shortening, oncogene expression, and DNA damage [1]
By assessing senescence-associated biomarkers in cancer cell lines cultured in stem cell medium (SCM), we found that similar senescence reprogramming is inherently part of the cancer stem cell phenotype
We tested the effects of SCM on human embryonic fibroblasts (MRC5 and WI-38) and found that it induced robust cellular senescence
Summary
Cellular senescence is a permanent cell proliferation arrest that is triggered by stress, which includes telomere shortening, oncogene expression, and DNA damage [1]. The activation of many tumor suppressor proteins are engaged in senescent cells, including p16INK4A, p15INK4B, p21CIP1, and p53 [3]. It has been demonstrated that cancer stem cells arise from senescent tumor cells that re-enter the cell cycle [6]. Cellular senescence is known to block normal functioning cells from adopting plasticity between cell fates. It prevents the generation of induced pluripotent stem cells (iPSCs) from adult fibroblasts [7]. It remains largely unknown how the senescence reprogramming process contributes to cancer stem cell formation
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