Abstract
Background
Prostate cancer is a major health issue affecting the male population worldwide, and its etiology remains relatively unknown. As presented on the Gene Expression Profiling Interactive Analysis database, acetyl-CoA acetyltransferase 1 (ACAT1) acts as a prostate cancer-promoting factor. ACAT1 expression in prostate cancer tissues is considerably higher than that in normal tissues, leading to a poor prognosis in patients with prostate cancer. Here, we aimed to study the role of the ACAT1-fused in sarcoma (FUS) complex in prostate cancer and identify new targets for the diagnosis and treatment of the disease.
Methods
We conducted immunohistochemical analysis of 57 clinical samples and in vitro and in vivo experiments using a mouse model and plasmid constructs to determine the expression of ACAT1 in prostate cancer.
Results
The relationship between the expression of ACAT1 and the Gleason score was significant. The expression of ACAT1 was higher in tissues with a Gleason score of > 7 than in tissues with a Gleason score of ≤7 (P = 0.0011). In addition, we revealed that ACAT1 can interact with the FUS protein.
Conclusions
In prostate cancer, ACAT1 promotes the expression of P62 and Nrf2 through FUS and affects reactive oxygen species scavenging. These effects are due to the inhibition of autophagy by ACAT1. That is, ACAT1 promotes prostate cancer by inhibiting autophagy and eliminating active oxygen species. The expression of ACAT1 is related to prostate cancer. Studying the underlying mechanism may provide a new perspective on the treatment of prostate cancer.
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Background
Prostate cancer is the second most frequently diagnosed malignancy and was the fifth leading cause of cancer-related deaths in men worldwide in 2020 [1, 2]. An increasing number of young men have been suffering from prostate cancer [3]. Therefore, the prevention and treatment of prostate cancer are essential. Commonly used treatment methods for prostate cancer include surgical treatment, non-invasive treatment, and androgen therapy [4,5,6]. With emerging treatment methods, such as immunotherapy and molecular therapy [7,8,9], the treatment of prostate cancer and the prognosis have improved. However, prostate cancer prevention and early treatment options are still research hotspots [10].
Acetyl-CoA acetyltransferase 1 (ACAT1) is an important enzyme [11,12,13,14,15,16,3].
In this study, we found that ACAT1 inhibited autophagy in prostate cells and exerted an ROS-scavenging effect. Both autophagy and increased ROS levels have certain tumor-inhibiting effects [27,28,29], and ACAT1 inhibits autophagy and eliminates intracellular ROS mainly by binding to FUS. FUS is an RNA-binding protein, which can promote the production of hnRNA in cells, thereby promoting the transcription of related genes [30]. In this study, we showed that FUS can promote the transcription of LC3B. LC3B is a key protein involved in autophagy. It mainly exists on the membrane of autophagosomes. When LC3A changes to LC3B, autophagosomes are formed. Furthermore, P62 binds to LC3B and autophagosomes on the membrane of a corpuscle; as the autophagosome enters the lysosome, it is degraded [31,32,33]. We believe that autophagy exerts cytotoxicity in prostate cancer. The results of the present study show that after binding to FUS, ACAT1 did not change FUS expression but inhibited FUS from entering the nucleus, thereby inhibiting the production of the autophagy-specific protein LC3B. We speculate that P62 accumulation might be caused by the damage that occurs in the later stages of autophagy [34], which prevents P62 from entering the autophagolysosome, and thereafter, its degradation. Nrf2 is located downstream of P62 [35, 36]. Nrf2 expression increased with the increase in P62 expression, and the active oxygen was scavenged.
Conclusions
Although the mechanism by which ACAT1 promotes prostate cancer has been demonstrated, the mechanism by which ACAT1 prevents FUS from entering the nucleus needs to be further explored. Furthermore, the underlying mechanism of how FUS affects LC3B transcription has not been elucidated and requires further investigation. Nonetheless, we demonstrated that the ACAT1-FUS complex plays a crucial role in prostate cancer development, which provides insights into the development of new therapeutic strategies by targeting or inhibiting the formation of this complex in prostate cancer.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- ACAT1:
-
Acetyl-CoA acetyltransferase 1
- ALS:
-
Amyotrophic lateral sclerosis
- FUS:
-
Fused in sarcoma
- GEPIA:
-
Gene expression profiling interactive analysis
- ROS:
-
Reactive oxygen species
- SPF:
-
Specific pathogen-free
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Acknowledgments
We thank Shanghai Wcgene Technology Co., Ltd. for providing the autophagy PCR array.
Funding
This work was supported by the National Natural Science Foundation of China (grant number 81874214) and National Natural Science Foundation of China Youth Foud (grant number 81702269). .
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JG designed the study, conducted the experiments, acquired and analyzed the data, and wrote the manuscript. XJ, YG, WZ, JL, YL, MC, and LF conducted the experiments and acquired the data. YZ and QL were responsible for the conception and supervision of the study and wrote the manuscript. All authors corrected the drafts and approved the final version of the manuscript.
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This study was approved by the Ethics Committee of China Medical University, and all patients signed informed consent forms. The study was carried out in compliance with the ARRIVE guidelines, and all procedures in animal experiments followed the ethical standards. All animal experiments were approved by the Institutional Animal Care and Use Committee of China Medical University and adhered to the guidelines for the care and use of laboratory animals issued by the China Animal Research Council.
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Supplementary Information
Additional file 1: Fig. S1.
ACAT1 is an oncogene in prostate cancer. A. Edu assay showing changes in the proliferation abilities of LNCaP and PC3 cells after an increase in ACAT1 expression. *P < 0.05, **P < 0.01. B. Transwell cell migration assay showing changes in the migration ability of LNCaP and PC3 cells after an increase in FUS expression. *P < 0.05, **P < 0.01.
Additional file 2: Fig. S2.
Associated expression of ACAT1 in prostate cancer cells. A. Expression of ACAT1 and FUS in four common prostate cancer cell lines (LNCaP, PC3, DU145, and 22RV1). The statistical analysis of gray values is shown. B. Expression of ACAT1 in the nucleus and cytoplasm. The statistical analysis of gray values is shown. *P < 0.05, **P < 0.01. C. In q-PCR assay, the mRNA levels of Nrf2 and P62 did not change significantly after an increase in ACAT1 expression in LNCaP cells and PC3 cells. D. In q-PCR assay, ACAT1 and FUS expression was increased in LNCaP and PC3 cells at the same time, whereas the mRNA levels of Nrf2 and P62 did not change significantly. E. Changes in autophagy-related protein expression after a decrease in ACAT1 expression. The statistical analysis of gray values is shown. *P < 0.05, **P < 0.01.
Additional file 3: Fig. S3.
Changes in the FUS protein level when ACAT1 and FUS expression is elevated simultaneously. A. Western blot showing changes in the FUS protein level in LNCaP cells when ACAT1 and FUS expression was elevated simultaneously. B. Western blot showing changes in the FUS protein level in PC3 cells when ACAT1 and FUS expression was elevated simultaneously.
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Guan, J., Jiang, X., Guo, Y. et al. Autophagy inhibition and reactive oxygen species elimination by acetyl-CoA acetyltransferase 1 through fused in sarcoma protein to promote prostate cancer. BMC Cancer 22, 1313 (2022). https://doi.org/10.1186/s12885-022-10426-5
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DOI: https://doi.org/10.1186/s12885-022-10426-5