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The dual role and mutual dependence of heme/HO-1/Bach1 axis in the carcinogenic and anti-carcinogenic intersection

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Abstract

Introduction

In physiological concentrations, heme is nontoxic to the cell and is essential for cell survival and proliferation. Increasing intracellular heme concentrations beyond normal levels, however, will lead to carcinogenesis and facilitate the survival of tumor cells. Simultaneously, heme in an abnormally high quantity is also a potent inducer of tumor cell death, contributing to its ability to generate oxidative stress on the cells by boosting oxidative phosphorylation and suppressing tumors through ferroptosis. During tumorigenesis and progression, therefore, heme works as a double-edged sword. Heme oxygenase 1 (HO-1) is the rate-limiting enzyme in heme catabolism, which converts heme into physiologically active catabolites of carbon monoxide (CO), biliverdin, and ferrous iron (Fe2+). HO-1 maintains redox equilibrium in healthy cells and functions as a carcinogenesis inhibitor. It is widely recognized that HO-1 is involved in the adaptive response to cellular stress and the anti-inflammation effect. Notably, its expression level in cancer cells corresponds with tumor growth, aggressiveness, metastasis, and angiogenesis. Besides, heme-binding transcription factor BTB and CNC homology 1 (Bach1) play a critical regulatory role in heme homeostasis, oxidative stress and senescence, cell cycle, angiogenesis, immune cell differentiation, and autoimmune disorders. Moreover, it was found that Bach1 influences cancer cells' metabolism and metastatic capacity. Bach1 controls heme level by adjusting HO-1 expression, establishing a negative feedback loop.

Materials and methods

Herein, the authors review recent studies on heme, HO-1, and Bach1 in cancer. Specifically, they cover the following areas: (1) the carcinogenic and anticarcinogenic aspects of heme; (2) the carcinogenic and anticarcinogenic aspects of HO-1; (3) the carcinogenic and anticarcinogenic aspects of Bach1; (4) the interactions of the heme/HO-1/Bach1 axis involved in tumor progression.

Conclusion

This review summarized the literature about the dual role of the heme/HO-1/Bach1 axis and their mutual dependence in the carcinogenesis and anti-carcinogenesis intersection.

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Funding

This project was supported by the National Natural Science Foundation of China (No. 81560580 and No. 81760377).

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  1. Jinjing Xu and Kuiyang Zhu contributed equally.

Authors and Affiliations

  1. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China

    Jinjing Xu & Jing Chen

  2. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China

    Jinjing Xu & Jing Chen

  3. Siyang Hospital, Suqian, 223700, China

    Kuiyang Zhu

  4. Jiangsu Huai’an Maternity and Children Hospital, Huai’an, 223001, China

    Yali Wang

  5. College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China

    Jing Chen

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All authors contributed to the study’s conception and design. JC, KZ, and YW performed material preparation, data collection, and analysis. JX wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Xu, J., Zhu, K., Wang, Y. et al. The dual role and mutual dependence of heme/HO-1/Bach1 axis in the carcinogenic and anti-carcinogenic intersection. J Cancer Res Clin Oncol 149, 483–501 (2023). https://doi.org/10.1007/s00432-022-04447-7

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