Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity

Zeng, Zhao-Lei; Wu, Ming-Wei; Sun, Jian; Sun, Yulin; Cai, Yuchen; Huang, Yijun; Xian, Li-Jian

doi:10.1093/jb/mvq069

Cited by 92 publications

(66 citation statements)

References 19 publications

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“…Another report showed that BMAL1-deficient fibroblasts have reduced sensitivity to the DNA damage-inducing anticancer drugs, etoposide and daunorubicin (8). Our previous study also demonstrated that Bmal1 plays a role involved in the effect of cisplatin in mice (33). In the present study, we found that Bmal1 overexpression induces G 2 -M phase arrest in HCT116 and THC8307 cell lines after oxaliplatin treatment, indicating that the DNA damage-repair signaling pathway is involved in this process.…”

Section: Discussionsupporting

confidence: 78%

Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

Zeng

Luo

Yang

et al. 2014

Clinical Cancer Research

127

110

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Purpose: The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer.Experimental Design: Three colorectal cancer cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of colorectal cancer cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of colorectal cancer cells to oxaliplatin. Flow cytometry was used to examine changes in the cell-cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived colorectal cancer tumors from patients treated with oxaliplatin-based regimens.Results: Bmal1 overexpression inhibited colorectal cancer cell proliferation and increased colorectal cancer sensitivity to oxaliplatin in three colorectal cancer cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of patients with colorectal cancer with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; P ¼ 0.043). The progression-free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; P ¼ 0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2-M arrest by activating the ATM pathway.Conclusion: Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.

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Section: Discussionsupporting

confidence: 78%

Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

Zeng

Luo

Yang

et al. 2014

Clinical Cancer Research

127

110

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“…In a recent study, loss of BMAL1 has been shown to reduce the expression of PER1, PER2, PER3, and p53 [27]. The downregulated circadian clock gene BMAL1 also accelerates the development of tumors and may influence the response to anti-cancer drugs [27]. Therefore, it is reasonable to hypothesize that circadian clock genes can regulate or suppress other circadian gene in the certain mechanism and this may also explain why most circadian genes (PER1, PER2, PER3, CRY1, CRY2, and BMAL1) are downregulated at the same time in HNSCC.…”

Section: Discussionmentioning

confidence: 91%

“…In HNSCC, the downregulated and disrupted circadian clock genes possibly lost their function of eliminating premalignant and malignant cells, hence leading to the accumulation of malignant cells and evolution of malignancies. In a recent study, loss of BMAL1 has been shown to reduce the expression of PER1, PER2, PER3, and p53 [27]. The downregulated circadian clock gene BMAL1 also accelerates the development of tumors and may influence the response to anti-cancer drugs [27].…”

Section: Discussionmentioning

confidence: 99%

Altered expression of circadian clock genes in head and neck squamous cell carcinoma

et al. 2011

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Head and neck squamous cell carcinoma (HNSCC) means a group of cancers developed from the upper aerodigestive tract, and 90% of them are squamous cell carcinomas. HNSCC is the tenth most commonly diagnosed form of cancer in males worldwide, but it is the seventh most common cause of cancer-related death. The circadian clock regulates daily rhythmic variations in various physiologic processes including sleep and activity, appetite, hormone levels, metabolism, and gene expression. Many recent studies have demonstrated that the disruption of circadian rhythm is associated with cancer development and tumor progression, such as chronic myeloid leukemia, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However the direct links between aberrant circadian clock gene expression and human malignancies, including HNSCC, remain largely unknown. In this study, the expression profiles of nine circadian clock genes of cancer tissue and noncancerous part from 40 patients of HNSCC were investigated. The expression of PER1, PER2, PER3, CRY1, CRY2, CKIε, and BMAL1 showed significant downregulation in the cancer tissues (p < 0.005). Downregulated PER3, CRY2, and BMAL1 expression was correlated with more advanced cancer stages (p < 0.05). Downregulated PER3 and upregulated TIM expression correlated with larger tumor size (p < 0.05), and lower expression of PER3 correlated with deeper tumor invasion (p < 0.05). Poor survival was related to lower expression of PER1 (p < 0.05) and PER3 (p < 0.01). These results indicate a possible association of circadian clock gene, especially PER3, expression with the pathogenesis of HNSCC.

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“…In support of human studies, experimental work in rodents documented accelerated tumor growth when mice, engrafted with lung adenocarcinoma or Glasgow osteosarcoma, were exposed to repeated jet lag conditions [9,10]. Similarly, enhanced tumor development has been described in mice with genetic disruption of the circadian clock (although this is not the case for all clock gene mutants) [9,[11][12][13] or surgical lesion of the central clock [14]. Taken together, circadian disruption coincides with increased carcinogenesis and faster tumor growth in a wide range of experimental setups.…”

Section: Circadian Clock Disruption Is Associated With Cancermentioning

confidence: 91%

“…In contrast to healthy cells with a cell-division rate of about 24 h, cancer cells are characterized by uncontrolled fast cell division. In fact, the literature reports that cell-cycle gene expression is altered in cancer cells [11,15] and that increased levels of the proto-oncogene Myc, upon mutation of clock genes in tumor cells, correlate with the cell-division speed [9]. Since the cell cycle is under circadian control, cancer cells might enhance their proliferation through manipulation of the circadian control over the cell cycle.…”

Section: Targeting the Clock In Tumors?mentioning

confidence: 99%

The tumor circadian clock: a new target for cancer therapy?

Kiessling

Cermakian

2017

Future Oncol.

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Cancer is among the most frequent causes of death in humans. To date, established cancer therapies include surgery, radiation, chemo-and immunotherapy as well as hormonal treatments up to stem cell transplantation. In this editorial, we highlight an additional and so far underestimated factor involved in carcinogenesis and prognosis, namely biological clocks, which should be carefully considered to establish future cancer therapies. Disruption of the circadian clock was documented both in host-tissue and in cancer cells, and functional oscillations were associated with cancer prognosis and survival. We summarize recent advances in the field of chronobiology regarding the role of the host's and tumor-intrinsic circadian clock functions in carcinogenesis.The biological circadian clock controls cancer-related pathways A central clock in the hypothalamus and peripheral clocks in almost all organs and tissues altogether regulate physiological processes in a time of day dependent (circadian) manner. The molecular bases of circadian clocks are cellular oscillations generated by a number of rhythmically expressed interconnected clock genes [1]. Highthroughput experiments on murine tissues showed that in any given cell-type or organ, hundreds or thousands of genes are expressed with a circadian rhythm, and led to the estimation that around 50% of all genes oscillate in at least one organ [2]. As a consequence of this, most cellular and physiological processes show 24 h oscillations. This is the case of many aspects of the immune system, including many immune cells and responses of relevance to cancer [3]. Also, major regulators of the cell cycle and tumor suppressor genes were shown to be regulated by the circadian clock, such as WEE1, c-MYC and p21 [4]. Consistently, cell-cycle progression and proliferation show circadian regulation. Circadian clock disruption is associated with cancerMismatch between the internal clock and the external time disrupts the circadian network, as reported for example in shift workers [5], and has been associated with a wide range of pathologies and disease states including cancer [4]. Mounting evidence from human-based epidemiological studies suggested an effect of circadian disruption during shift work on cancer risk. For example, the risk to develop breast cancer was extensively increased in nurses exposed to long-term rotating night shift work [6]. Similar results were obtained for prostate cancer risk in night shift workers [7]. Out of note, in 2007 an agency of the WHO has classified night shift work leading to circadian disruption as 'probably carcinogenic' to humans [8]. Since then, there has been growing interest in understanding how circadian disruption may play a role in cancer development and progression. In support of human studies, experimental work in rodents documented accelerated tumor growth when mice, engrafted with lung adenocarcinoma or Glasgow osteosarcoma, were exposed to repeated jet lag conditions [9,10]. Similarly, enhanced tumor development has been described in mi...

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Effects of the biological clock gene Bmal1 on tumour growth and anti-cancer drug activity

Cited by 92 publications

References 19 publications

Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

Altered expression of circadian clock genes in head and neck squamous cell carcinoma

The tumor circadian clock: a new target for cancer therapy?

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