Switch of NF-YA splice variants in prostate cancer development and progression

The pioneer transcription factor NF-Y is a heterotrimer composed by NF-YA, -YB and -YC subunits: NF-YA is the limiting subunit and harbors the DNA CCAAT-box binding domain. NF-Y is a master transcriptional regulator that ensures proper cell proliferation, controlling cell cycle, DNA replication, apoptosis and metabolism. Recent analyses pointed out that NF-Y binding site is over-represented in promoters of genes overexpressed during the progression from benign epithelium to Prostate Cancer (PC). Moreover, cell cycle regulation genes have emerged as a signature that can discriminate between metastatic and benign prostate tissues. The analysis of TCGA-RNAseq data highlighted a slight but significant increase of NF-YA levels in PC tumor vs normal tissues, particularly in high Gleason score specimens. Since the NF-YA gene encodes for two splice isoforms, NF-YAl (long) and NF-YAs (short), we generated untransformed and cancer prostate cell lines stably over-expressing NF-YA isoforms, to dissect the functional role of NF-YA in PC development and progression. Our data indicate that NF-YAl and NF-YAs could play different activities in cancer-associated processes, such as clonogenic ability, anchorage-independent growth, 3D cell growth, migration and invasion. In particular, in cancer cells NF-YAl improves invasion ability, while NF-YAs seems to enhance the proliferation of tumor spheroids. These results are consistent with increased NF-YAs/NF-YAl splice ratio observed in the progression from normal to malignant prostatectomy samples. Besides, normal prostate cell lines preferentially express the long NF-YA isoform, while an increase in NF-YAs/NF-YAl ratio can be observed in PC cell lines. These results prompt us to speculate that NF-YAl could participate to metastatization, while NF-YAs could have a major role in tumor growth and colonization. Disclosing this dualism could be crucial to better stratify PC patients and identify new specific anti-cancer treatments.