Abstract
Dormant cancer cells drive recurrence and drug resistance, which lead to poor prognosis in colorectal cancer (CRC). The mechanisms that regulate the entry of cancer cells into dormancy remain to be extensively studied. Nanog is a master transcription factor to maintain the self-renewal and pluripotency of stem cells. Since dormant cancer cells are similar to quiescent cancer stem cells, the correlation between dormant state and Nanog in CRC is worth to be explored. Serum deprivation is a common method to establish experimental cellular dormancy model. Here, we verified that serum deprivation-induced CRC cells to enter a cellular dormancy state, characterized by no proliferation, no death, no senescence, resistance to chemotherapy, high expression of dormant markers, metabolic suppression, and recovery to active status. Interestingly, we further identified that Nanog was upregulated in dormant CRC cells. Nanog knockdown could destroy the dormant state of serum-deprived CRC cells while Nanog overexpression could induce dormancy in CRC cells. Mechanistically, Nanog was regulated through a fatty acid oxidation (FAO)/ATP citrate lyase (ACLY)-dependent pathway. FAO increased ACLY expression to promote the synthesis of acetyl-CoA, which was transferred by P300 to accelerate H3K27 acetylation of Nanog promoter. Then, Nanog upregulation increased the transcription of P21 and P27, which promoted the dormancy of CRC cells. Our findings revealed that Nanog could induce cellular dormancy in CRC cells and unlocked a specific mechanism to govern the process.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies worldwide
A study demonstrated that IFN-γ induced tumor-repopulating cells (TRCs) to enter dormancy to evade immunotherapy, which was mediated by an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway [7]
In the group SF CRC cells treated with the results indicated that Nanog performed as a transcription factor to chemotherapeutics 5-fluorouracil (5-FU), the apoptosis rate of enhance the expression of P21 and P27, and induced the which was significantly lower than that of normal conditions (NC) cells treated with 5- cellular dormancy of CRC cells
Summary
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Insight into colorectal carcinogenesis and development provides systemic and individual treatment options for CRC patients, such as chemo-radiotherapy, targeted therapy and immunotherapy [1]. The orphan nuclear receptor COUP-TF1 and DEC2 [8, 9], as well as the cell cycle regulating proteins P21 and P27 [10] have been identified as tumor cell dormancy markers In addition to these molecular markers, cellular dormancy can be functionally defined as G0/G1 arrest, being neither dead nor senescent, consuming less glucose, metabolic suppression, decreasing responses to stimulation, and regrowth once the dormancy stimuli are removed [11]. Our previous study has shown that Nanog promoted the growth and self-renewal of colorectal cancer stem cells [14]. Showed that serum deprivation-induced CRC cells to enter a cellular dormancy state.
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