TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma

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Abstract

Background

Oral squamous cell carcinoma (OSCC), the predominant malignancy of the oral cavity, is characterized by high incidence and low survival rates. Emerging evidence suggests a link between circadian rhythm disruptions and cancer development. The circadian gene TIMELESS, known for its specific expression in various tumors, has not been extensively studied in the context of OSCC. This study aims to explore the influence of TIMELESS on OSCC, focusing on cell growth and metabolic alterations.

Methods

We analyzed TIMELESS expression in OSCC using western blot, immunohistochemistry, qRT-PCR, and data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). The role of TIMELESS in OSCC was examined through clone formation, MTS, cell cycle, and EdU assays, alongside subcutaneous tumor growth experiments in nude mice. We also assessed the metabolic impact of TIMELESS by measuring glucose uptake, lactate production, oxygen consumption, and medium pH, and investigated its effect on key metabolic proteins including silent information regulator 1 ( SIRT1), hexokinase 2 ( HK2), pyruvate kinase isozyme type M2 ( PKM2), recombinant lactate dehydrogenase A ( LDHA) and glucose transporter-1 (GLUT1).

Results

Elevated TIMELESS expression in OSCC tissues and cell lines was observed, correlating with reduced patient survival. TIMELESS overexpression enhanced OSCC cell proliferation, increased glycolytic activity (glucose uptake and lactate production), and suppressed oxidative phosphorylation (evidenced by reduced oxygen consumption and altered pH levels). Conversely, TIMELESS knockdown inhibited these cellular and metabolic processes, an effect mirrored by manipulating SIRT1 levels. Additionally, SIRT1 was positively associated with TIMELESS expression. The expression of SIRT1, HK2, PKM2, LDHA and GLUT1 increased with the overexpression of TIMELESS levels and decreased with the knockdown of TIMELESS.

Conclusion

TIMELESS exacerbates OSCC progression by modulating cellular proliferation and metabolic pathways, specifically by enhancing glycolysis and reducing oxidative phosphorylation, largely mediated through the SIRT1 pathway. This highlights TIMELESS as a potential target for OSCC therapeutic strategies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-023-04791-3.

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Most cited references 33

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The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

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Rebecca L Siegel, Kimberly D Miller, Nikita Sandeep Wagle … (2023)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.

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Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

Zhen Dong, Guoxin Zhang, Meng Qu … (2019)

Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSCs). Here, we show that GSCs, differentiated glioblastoma cells (DGCs), and non-malignant brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell cycle arrest and apoptosis. Chromatin immunoprecipitation revealed BMAL1 preferentially bound at metabolic genes in GSCs, associated with differences in active chromatin regions compared to NSCs. Targeting BMAL1 or CLOCK attenuated mitochondrial metabolic function and reduced expression of the tricarboxylic acid (TCA) cycle enzymes. Small molecule agonists of two independent BMAL1::CLOCK negative regulators, the Cryptochromes and REV-ERBs, downregulated stem cell factors and reduced GSC growth. Combination of Cryptochrome and REV-ERB agonists induced synergistic anti-tumor efficacy. Collectively, GSCs coopt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms.

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Author and article information

Contributors

Hui Zhang: 85451683@qq.com

Jingtao Chen:

ORCID: http://orcid.org/0009-0008-2965-3108

cjt19840713@163.com

Peng Yuan:

ORCID: http://orcid.org/0000-0001-5040-3914

yuanpeng834700@126.com

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 4 January 2024

Publication date PMC-release: 4 January 2024

Publication date Collection: 2024

Volume: 22

Electronic Location Identifier: 21

Affiliations

[1 ]GRID grid.460007.5, ISNI 0000 0004 1791 6584, Department of Nuclear Medicine, , Tangdu Hospital, Air Force Medical University, ; 569 Xinsi Road, Xi’an, 710038 Shaanxi China

[2 ]Department of Clinical Laboratory, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, ( https://ror.org/01dr2b756) Shiyan, 442008 Hubei China

[3 ]GRID grid.460007.5, ISNI 0000 0004 1791 6584, Department of Interventional Radiology and Pain Treatment, , Tangdu Hospital, Air Force Medical University, ; Xi’an, 710038 Shaanxi China

[4 ]Xi’an Physical Education University, ( https://ror.org/00pt5by23) Xi’an, 710068 Shaanxi China

[5 ]The First Clinical Medical College, Shaanxi University of Chinese Medicine, ( https://ror.org/021r98132) Xianyang, 712046 Shaanxi China

[6 ]School of Nursing and Rehabilitation, Xi’an Medical University, ( https://ror.org/01fmc2233) Xi’an, 710021 Shaanxi China

[7 ]Medical College of Ankang University, ( https://ror.org/053ax8j41) Ankang, 725000 Shaanxi China

[8 ]The Second Clinical Medical School, Shaanxi University of Chinese Medicine, ( https://ror.org/021r98132) Xianyang, 712046 Shaanxi China

[9 ]GRID grid.460007.5, ISNI 0000 0004 1791 6584, Department of Stomatology, , Tangdu Hospital, Air Force Medical University, ; 569 Xinsi Road, Xi’an, 710038 Shaanxi China

[10 ]Department of Ultrasound Diagnosis, Xi’an Children’s Hospital, ( https://ror.org/04595zj73) 69 West Park Lane, Xi’an, 710002 Shaanxi China

Author information

Jingtao Chen http://orcid.org/0009-0008-2965-3108

Peng Yuan http://orcid.org/0000-0001-5040-3914

Article

Publisher ID: 4791

DOI: 10.1186/s12967-023-04791-3

PMC ID: 10768318

PubMed ID: 38178094

SO-VID: afaf1251-c419-4a72-b6e4-edf6ac8e61b6

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 17 September 2023

Date accepted : 9 December 2023

Funding

Funded by: Peng Yuan

Award ID: 2023-JC-YB-671

Award Recipient : Yafan Chen

Funded by: Jingtao Chen

Award ID: 2022JM-592

Award Recipient : Jingtao Chen

Funded by: Hui Zhang

Award ID: 2022JQ-930

Award Recipient : Hui Zhang

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: oral squamous cell carcinoma (oscc),timeless,glucose metabolism,sirt1

Data availability:

ScienceOpen disciplines: Medicine

Keywords: oral squamous cell carcinoma (oscc), timeless, glucose metabolism, sirt1

TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma

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Supplementary Information

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Most cited references 33

Hallmarks of Cancer: The Next Generation

Cancer statistics, 2023

Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

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