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Open Access Publications from the University of California

Scholarly Works (34 results)

  • Article
  • Peer Reviewed
UC Irvine Previously Published Works (2015)

Purpose of review

The circadian clock is an intricate biological timekeeper that is subject to fine-tuning mechanisms in order to maintain synchrony with the surrounding environment. One such mechanism is performed by the mammalian sirtuins that provide plasticity to the circadian clock by sensing cellular metabolic state. The sirtuins modulate the circadian epigenome and subsequent transcriptional control, and alterations to this organized system manifest in metabolic consequences, aging phenotypes and possibly cancer.

Recent findings

New information regarding sirtuin-dependent control of the circadian clock has emerged. In addition to sirtuin (SIRT)1 and SIRT3, SIRT6 has been demonstrated as a critical regulator of circadian transcription that also serves as an interface with metabolic homeostasis. Also, new metabolic functions of SIRT1 have been described in the brain, which are critical to relay nutritional inputs to the central clock.

Summary

This review focuses on the link between the circadian clock and the sirtuins, with an emphasis on new findings. In addition, speculation on the possible connections at the physiological level will be made that could further link the clock to aging and cancer.
    Cover page: Sirtuin-dependent clock control
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2019)
    The circadian clock is a biological mechanism that dictates an array of rhythmic physiological processes. Virtually all cells contain a functional clock whose disruption results in altered timekeeping and detrimental systemic effects, including cancer. Recent advances have connected genetic disruption of the clock with multiple transcriptional and signaling networks controlling tumor initiation and progression. An additional feature of this circadian control relies on cellular metabolism, both within the tumor microenvironment and the organism systemically. A discussion of major advances related to cancer metabolism and the circadian clock will be outlined, including new efforts related to metabolic flux of transformed cells, metabolic heterogeneity of tumors, and the implications of circadian control of these pathways.
      Cover page: Circadian Clocks and Cancer: Timekeeping Governs Cellular Metabolism
      • Thesis
      • Peer Reviewed
      UC Irvine Electronic Theses and Dissertations (2024)

      The circadian clock is the internal biological pacemaker that regulates critical cellular processes including immunity, metabolism, and cell cycle control. Disruption of the circadian clock has been shown to increase the risk of cancer development and progression; however, the underlying mechanism requires further investigation. Our lab has developed a novel genetically engineered mouse model to study the impact of circadian clock disruption on colorectal cancer. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc-driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity and subsequent Wnt hyperactivation. Stinkingly, we found that transformation into spheroids is associated with a fetal-progenitor signature that drives reprogramming of the circadian clock. A fetal-progenitor signature and circadian reprogramming were also found in human colon tumors. Utilizing RNA-sequencing analysis, we defined a combined circadian clock and fetal risk score that accurately predicts patient survival. Overall, our findings demonstrate a previously unidentified link between a fetal-progenitor state and circadian reprogramming in CRC that is associated with late-stage disease.

      Additionally, the role of circadian control of antitumor immunity in colorectal cancer progression is not well understood. To address this, we used a single-cell RNA sequencing approach and found that circadian clock disruption promotes the accumulation of immunosuppressive myeloid cells and subsequent suppression of cytotoxic CD8+ T cells. Epithelial cell clock disruption promotes secretion of inflammatory cytokines and recruits immunosuppressive myeloid cells. Lastly, we demonstrated that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive myeloid cells. Collectively, this suggests that circadian control of tumor immunosuppression affects the efficacy of immune checkpoint blockade.

        Creative Commons 'BY-NC-ND' version 4.0 license
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2018)
        The circadian clock is a complex cellular mechanism that, through the control of diverse metabolic and gene expression pathways, governs a large array of cyclic physiological processes. Epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer that is supported by recent preclinical data. In addition, results from animal models and molecular studies underscore emerging links between cancer metabolism and the circadian clock. This has implications for therapeutic approaches, and we discuss the possible design of chronopharmacological strategies.
          Cover page: The emerging link between cancer, metabolism, and circadian rhythms
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2022)
          Isolation of primary hepatocytes and culturing these cells ex vivo provides a powerful platform to model liver physiology in vivo. Primary hepatocytes can be cultured for several days, the circadian clock can be synchronized, and these primary cells can be utilized for functional gene regulation analysis and metabolic studies. In this chapter, we describe detailed methodology for isolation of viable primary hepatocytes, techniques for culturing these cells, methods for synchronization of the circadian clock, transfection and luciferase reporter analysis, as well as glucose production assays as a functional readout of metabolic state.
            Cover page: Circadian Control of Transcriptional and Metabolic Rhythms in Primary Hepatocytes
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2013)
            The circadian clock governs biological timekeeping on a systemic level, helping to regulate and maintain physiological processes, including endocrine and metabolic pathways with a periodicity of 24-hours. Disruption within the circadian clock machinery has been linked to numerous pathological conditions, including cancer, suggesting that clock-dependent regulation of the cell cycle is an essential control mechanism. This review will highlight recent advances on the 'gating' controls of the circadian clock at various checkpoints of the cell cycle and also how the cell cycle can influence biological rhythms. The reciprocal influence that the circadian clock and cell cycle exert on each other suggests that these intertwined biological circuits are essential and multiple regulatory/control steps have been instated to ensure proper timekeeping.
              Cover page: The circadian clock and cell cycle: interconnected biological circuits
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2015)

              Purpose of review

              The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.

              Recent findings

              The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.

              Summary

              This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.
                Cover page: Circadian clocks, epigenetics, and cancer
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2023)
                Circadian clock dysregulation has been implicated in various types of cancer and represents an area of growing research. However, the role of the circadian clock in prostate cancer has been relatively unexplored. This literature review will highlight the potential role of circadian clock dysregulation in prostate cancer by examining molecular, epidemiologic, and clinical data. The influence of melatonin, light, night shift work, chronotherapy, and androgen independence are discussed as they relate to the existing literature on their role in prostate cancer.
                  Cover page: Circadian Clock Dysregulation and Prostate Cancer: A Molecular and Clinical Overview
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2016)
                  Liver regeneration offers a distinctive opportunity to study cell proliferation in vivo Mammalian silent information regulator 1 (SIRT1), a NAD+-dependent histone deacetylase, is an important regulator of various cellular processes, including proliferation, metabolism, and circadian rhythms. In the liver, SIRT1 coordinates the circadian oscillation of clock-controlled genes, including genes that encode enzymes involved in metabolic pathways. We performed partial hepatectomy in WT and liver-specific Sirt1-deficient mice and analyzed the expression of cell cycle regulators in liver samples taken at different times during the regenerative process, by real time PCR, Western blotting analysis, and immunohistochemistry. Lipidomic analysis was performed in the same samples by MS/HPLC. We showed that G1/S progression was significantly affected by absence of SIRT1 in the liver, as well as circadian gene expression. This was associated to lipid accumulation due to defective fatty acid beta-oxidation. Our study revealed for the first time the importance of SIRT1 in the regulation of hepatocellular proliferation, circadian rhythms, and lipid metabolism during liver regeneration in mice. These results represent an additional step toward the characterization of SIRT1 function in the liver.
                    Cover page: Histone Deacetylase SIRT1 Controls Proliferation, Circadian Rhythm, and Lipid Metabolism during Liver Regeneration in Mice*
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2010)
                    Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of hormone refractory cell lines identified 115 differentially regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. A group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and selectively up-regulated in the letrozole-resistant cell lines. Human miR-128a was predicted to target the TGFβ signaling pathway and indeed sensitivity to TGFβ was compromised in the letrozole-resistant cells, as compared to parental MCF-7aro. Human miR-128a was shown to negatively target TGFβRI protein expression by binding to the 3'UTR region of the gene. Inhibition of endogenous miR-128a resulted in resensitization of the letrozole-resistant lines to TGFβ growth inhibitory effects. These data suggest that the hormone-responsive miR-128a can modulate TGFβ signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFβ signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance.
                      Cover page: The role of microRNA-128a in regulating TGFbeta signaling in letrozole-resistant breast cancer cells
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