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Targeting DGAT1 inhibits prostate cancer cells growth by inducing autophagy flux blockage via oxidative stress

Oncogene volume 43, pages 136–150 (2024)Cite this article

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Abstract

Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa.

Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor.

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Fig. 1: DGAT1 upregulation associates with tumor grade, stage, and metastasis in PCa.
Fig. 2: DGAT1, but not DGAT2, promotes lipid droplet formation and tumor cell growth.
Fig. 3: DGAT1 functions as an oncoprotein in PCa by promoting autophagy flux.
Fig. 4: DGAT1 is a key regulator in maintaining mitochondrial homeostasis and the excessive ROS production induced by DGAT1 inhibition contributes to autophagy flux blockage in PCa cells.
Fig. 5: Inhibition of DGAT1 significantly inhibits PCa tumor growth and induces autophagy flux blockage in vivo.
Fig. 6: Fenofibrate induces mitochondrial oxidative stress, autophagy flux blockage, and inhibits cells growth in PCa is partially due to the inhibition of DGAT1, in vitro and in vivo.

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Data are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Professor Xin Zhou (The Institute of Cancer Research of Jilin University) for helpful discussions and his valuable assistance in revising the paper.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82272993 and 81972372 belonging to XG), the grant from Jilin Medical and Health Talent Project (JLSCZD2019-016 belonging to GW), the grant from the Department Science and Technology Department of Jilin Province (20190901006JC, YDZJ202202CXJD042 belonging to GW and 20210101355JC belonging to TZ), the grant from the Doctor of excellence program of the First Hospital of Jilin University (JDYY-DEP-2022021 belonging to HC), the grant from the 14th Youth Project of the First Hospital of Jilin University (JDYY14202301 belonging to HC).

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Author notes

  1. These authors contributed equally: Tong Zhou, Limei Qu.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China

    Haiying Cui, Tong Zhou, Mingyue Han, Xinhua Ren, Guixia Wang & Xiaokun Gang

  2. Department of Orthopedics, The Second Hospital Jilin University, Changchun, 130021, Jilin Province, China

    Yao Wang

  3. Department of Pathology, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China

    Limei Qu

  4. Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China

    Xiaoling Zhang

  5. Department of Urology, Jilin Oncological Hospital, Changchun, 130021, Jilin Province, China

    Yingdi Wang

  6. Department of Clinical Nutrition, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China

    Shuo Yang

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Contributions

Conception and design: HC, GW and XG; Development of methodology: HC, YW, TZ, XZ, MH, XR and YW; Acquisition of data: HC, YW, TZ, YW, MH; Analysis and interpretation of data: HC, MH, XR, YW and YW; Writing, review, and/or revision of the manuscript: HC, SY, GW and XG; Administrative, technical, or material support: HC, YW, TZ, GW and XG; Study supervision: GW and XG.

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Correspondence to Guixia Wang or Xiaokun Gang.

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Human samples study was approved by the First Hospital of Jilin University Ethics Reviews Board. The patients were given written informed consent to take part, and patients consented to the use of material and clinical information for research purposes. Subcutaneous xenograft study was approved by the First Hospital of Jilin University of Animal Ethics Committee.

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Cui, H., Wang, Y., Zhou, T. et al. Targeting DGAT1 inhibits prostate cancer cells growth by inducing autophagy flux blockage via oxidative stress. Oncogene 43, 136–150 (2024). https://doi.org/10.1038/s41388-023-02878-1

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