Gastric cancer (GC) is the fifth commonest malignant tumor in the world, which ranks third in all cancer-related deaths [1]. With a deeper understanding of the pathogenesis of GC, advances have been made in therapeutic strategies such as surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy [2]. However, patients suffering from advanced GC remains have poor prognosis due to metastasis, with a five-year survival rate of less than 30% [3]. Radiotherapy has been verified to be effective in controlling the local recurrence rate after surgery and improving the prognosis of partial GC patients [4]. However, radioresistance seriously reduces the therapeutic effect. A previous study has revealed that radiotherapy-induced intracellular changes could facilitate tumor metastasis [5]. Therefore, it is of great significance to explore molecular mechanisms underlying tumor metastasis and radioresistance.

In this report, we screened the differentially dysregulated mRNAs in the blood samples of GC patients with peritoneal metastasis from gene expression omnibus (GEO) database, identifying the most significantly upregulated mRNA cytochrome P450 1B1 (CYP1B1). As a metabolic enzyme, CYP1B1 has been reported in various human cancers due to its oncogenic properties. For example, CYP1B1 augments the mesenchymal and chemoresistant phenotypes of triple-negative breast cancer cells [6]. CYP1B1 degrades ACSL4 to suppress ferroptosis and promotes anti-PD-1 resistance in colorectal cancer [7]. A previous study has shown that CYP1B1 can be upregulated by lncRNA UCA1 to suppress apoptosis and enhance cisplatin resistance in GC [8]. However, it has been unexplored whether CYP1B1 can act as a metastatic regulator and a radioresistant modulator in GC.

Transcriptional enhancers can activate the transcription of neighboring genes by binding RNA Pol II, transcription factors and co-regulators [9]. According to the first report in 2013, super-enhancers consist of clusters of enhancers, and selectively localize at cell identity gene and critical oncogene loci [10,11]. Super-enhancers are characterized by massive acetylated histone H3 lysine 27 (H3K27ac) signals, which are densely bound by mediators, co-regulators, and master transcription factors [[12], [13], [14], [15]]. The histone acetyltransferase p300 has been widely reported as a transcription regulator that exerts functions in transcription activation by enhancing the H3K27ac level in the promoter of its downstream targets [16]. YY1 is a transcription factor that has been reported to be able to transcriptionally activate downstream target genes [17,18]. Moreover, YY1 can form transcription complexes with other transcription factors to jointly act on the transcriptional activation of downstream targets [19]. Importantly, studies have confirmed that YY1 can form a transcriptional complex with p300 to regulate the transcriptional levels of downstream target genes [20]. To date, studies have not explored whether YY1/p300 complex can regulate the transcription activity of CYP1B1. This study tries to investigate whether the YY1/p300 complex-induced H3K27ac enrichment in CYP1B1 promoter to upregulate CYP1B1 in highly metastatic GC cells.

Cytochrome P450 enzymes (CYPs) have been extensively studied for their roles in drug resistance and metabolism. CYP1B1 has been reported as a critical regulator of lipid metabolism and fatty acid metabolism [21,22]. Tumor cells upregulate de novo fatty acid synthesis pathways by increasing fatty acid synthase expression to meet the demands of rapid proliferation for membrane biosynthesis and energy supply, thereby promoting tumor metastasis and drug resistance [23]. p38 MAPK signaling pathway is closely associated with fatty acid metabolism [24,25]. Phosphorylation-activated downstream transcription factors of p38 MAPK pathway initiate cellular processes including proliferation, differentiation, inflammation, and apoptosis. However, whether CYP1B1 can regulate fatty acid metabolism in GC via p38 MAPK pathway remains unclear. Previous studies have demonstrated that ARNT can activate p38 MAPK pathway to confer drug resistance in glioma [26]. Mechanistically, CYP1B1 has been shown to prevent ubiquitin-proteasome-mediated degradation of XIAP protein [27]. Nevertheless, it is unclear whether the CYP1B1/ARNT axis affects the activity of p38 MAPK pathway to regulate fatty acid metabolism of GC cells. This study further explores whether CYP1B1 can regulate fatty acid metabolism by affecting ARNT protein stability to activate p38 MAPK pathway.

In summary, this study aims to reveal the functions of CYP1B1 in metastasis and radioresistance of GC cells. Moreover, this study focuses on YY1/p300 complex-induced H3K27ac enrichment in CYP1B1 promoter and the role of CYP1B1 in modulating p38 MAPK-mediated fatty acid metabolism.