Physiological expression of
cyclin A1, a unique cell cycle regulator essential for spermatogenesis, is predominantly restricted in male germ cells. Outstandingly, previous studies have also demonstrated the abnormal expression of
cyclin A1 in various human
tumors. How male germ cell-specific
cyclin A1 is transcriptionally activated in
tumor cells, however, is elusive. To begin to understand the molecular mechanisms governing the ectopic expression of
cyclin A1, we searched for
transcription factors and cis-regulatory
DNA elements. We found that overexpression of PITX2, a paired-like homeodomain
transcription factor and a downstream effector of Wnt/β-
catenin signaling, resulted in upregulation of
cyclin A1 in HEK293 cells and TPC-1
thyroid cancer cells. On the other hand, PITX2 knockdown in TPC-1 cells caused reduced
cyclin A1. Promoter reporter assays with a series of deletion constructs determined that the
DNA element from -102 to -96 bp of the
cyclin A1 promoter is responsible for PITX2-induced gene expression. The result of
chromatin immunoprecipitation revealed the occupancy of PITX2 on the
cyclin A1 promoter. Taken together, these findings demonstrate that
cyclin A1 is a transcriptional target of PITX2. Consistently, our immunohistochemistry result showed up-regulation of
cyclin A1 in human
papillary thyroid carcinoma, where overexpressed PITX2 has been endorsed in our recent report. Thus, our study provides new evidence on the regulation of
cyclin A1 gene expression and offers a PITX2-cycin A1 pathway for cell cycle regulation.