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.
Highlights
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
The present study demonstrated several novel findings. 4F2hc expression seems to be one of the promising therapeutic targets in prostate cancer (PC)
SKP2 was newly identified as a novel target of 4F2hc
Summary
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. Several lines of evidence have shown that nutrient transporters are upregulated in cancer cells while supporting large-scale growth and r eproduction[13]. L-type amino acid transporter 1 (LAT1, SLC7A5), a systemic L amino acid transporter, requires a covalent association with 4F2 cell-surface antigen heavy chain (4F2hc,SLC3A2) for its functional expression in the Scientific Reports | (2021) 11:11478. LAT1, which has been shown to bind to 4F2hc, is abundantly expressed in various types of cancers, including non-small cell lung cancer, breast cancer, biliary tract cancer, pancreatic cancer, and prostate cancer[15,16,17,18,19]. Upregulation of 4F2hc through AR-V7 contributes to the progression of C RPC23
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