Abstract
Disruption of circadian rhythms has been implicated in an increased risk for cancer development. The Period2 (Per2) gene encodes one of the major components of the mammalian circadian clock, which plays a key role in controlling the circadian rhythms in physiology and behavior. PER2 has also been reported to suppress the malignant transformation of cells, but its role in the regulation of cancer susceptibility to chemotherapeutic drugs remains unclear. In this study, we found that oncogene-transformed embryonic fibroblasts prepared from Per2-mutant (Per2m/m ) mice, which are susceptible to both spontaneous and radiation-induced tumorigenesis, were resistant against common chemotherapeutic drugs and that this resistance is associated with up-regulation of the aldehyde dehydrogenase 3a1 (Aldh3a1) gene. Co-expression of the oncogenes H-rasV12 and SV40 large T-antigen induced malignant transformation of both WT and Per2m/m cells, but the cytotoxic effects of the chemotherapeutic agents methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin were significantly alleviated in the oncogene-transformed Per2m/m cells. Although introduction of the two oncogenes increased the expression of Aldh3a1 in both WT and Per2m/m cells, the ALDH3A1 protein levels in the Per2m/m cells were ∼7-fold higher than in WT cells. The elevated ALDH3A1 levels in the oncogene-transformed Per2m/m cells were sufficient to prevent chemotherapeutic drug-induced accumulation of reactive oxygen species. Consequently, shRNA-mediated suppression of Aldh3a1 expression relieved the chemoresistance of the Per2m/m cells. These results suggest a role for mutated PER2 in the development of multiple drug resistance and may inform therapeutic strategies for cancer management.
Highlights
Disruption of circadian rhythms has been implicated in an increased risk for cancer development
We found that oncogene-transformed embryonic fibroblasts prepared from Per2-mutant (Per2m/m) mice, which are susceptible to both spontaneous and radiation-induced tumorigenesis, were resistant against common chemotherapeutic drugs and that this resistance is associated with up-regulation of the aldehyde dehydrogenase 3a1 (Aldh3a1) gene
Per2 has a critical role in controlling the malignancy of cancers [17, 34], our results showed a mechanism regulating the resistance of oncogene-transformed Per2m/m cells against the cytotoxicity of chemotherapeutic drugs
Summary
Oncogene-transformed Per2m/m cells resist the cytotoxicity of chemotherapeutic drugs. Intracellular accumulation of MTX, GEM, VP-16, VCR, and L-OHP was not significantly different between WT and Per2m/m cells (Fig. 1E, right panels), suggesting that the tolerance of the oncogene-transformed Per2m/m cells to the chemotherapeutic drugs is not due to the function of efflux transporters. The binding amounts of both HDACs around the transcriptional start site of the Aldh3a1 gene were significantly decreased in oncogene-transformed Per2m/m cells (Fig. 4E), recruiting p300/CBP-associated factor (PCAF) was comparable between WT and Per2m/m cells. Taken together, these data support a model in which PER2 acts as a repressor of oncogene-induced Aldh3a1 expression through recruitment of HDACs to the promoter region. Dysfunction of PER2 appears to allow H3K9 acetylation, leading to enhancement of oncogene-induced expression of ALDH3A1 (Fig. 5)
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