The heavy chain of 4F2 antigen promote prostate cancer progression via SKP-2

Abstract

The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc’s impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.

GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis

“…Again, using a tumor tissue array containing patient samples, we stained for p-GCN2 and SLC3A2 (4F2). Similar to recent findings [47], SLC3A2 (4F2) staining was increased in malignant tissue samples as compared to normal tissue ( Supplementary Figure 21A ). Interestingly, SLC3A2 (4F2) showed a moderate, albeit significant, correlation with expression of p-GCN2 (r = 0.27, p = 0.025).…”

Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways

“…It is obvious that LAT1 and 4F2hc cannot work alone without each other. Meanwhile, in many forms of cancer, increased 4F2hc expression levels have been linked to a worse prognosis in several studies [ 24 , 25 , 26 , 27 ]. The most critical structure involved in the interaction of the complex is the disulfide bond between the two proteins [ 8 , 23 ].…”

“…Similarly, in human neoplasms such as prostate cancer, gastric cancer, lung pleomorphic carcinoma, and neuroendocrine carcinoma, 4F2hc expression is upregulated [ 24 , 27 , 41 , 55 ]. Increased 4F2hc expression is linked to a worse chance of survival, cell proliferation, and metastasis [ 56 ].…”

“…4F2hc and LAT1 expression in PCa tissue and association with clinical variables. The expression levels (4F2hc and LAT1/high and low) are associated with various tumor prognoses [ 24 ]. The data from the same study [ 24 ] revealed that SKP-2 is a downstream and particular target gene of 4F2hc.…”

“…The expression levels (4F2hc and LAT1/high and low) are associated with various tumor prognoses [ 24 ]. The data from the same study [ 24 ] revealed that SKP-2 is a downstream and particular target gene of 4F2hc. SKP-2 is associated with cell cycle, DNA replication, and cell division.…”