The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1

Abstract

Homeobox genes constitute a large family of transcription factors that are essential during normal development and are often dysregulated in cancer. However, the molecular mechanisms by which homeobox genes influence cancer remain largely unknown. Here we show that the tissue-restricted cyclin A1 is a transcriptional target of the Six1 homeoprotein. Both genes are expressed in the embryonic but not the terminally differentiated mammary gland, and Six1-knockout mice show a dramatic reduction of cyclin A1 in the embryonic mammary gland. In addition, both genes are reexpressed in breast cancers. Six1 overexpression increases cyclin A1 mRNA levels and activity, cell proliferation, and tumor volume, whereas Six1 down-regulation decreases cyclin A1 mRNA levels and proliferation. Overexpression of Six1 in wild-type mouse embryonic fibroblasts, but not in knockout variants lacking the cyclin A1 gene, induces cell proliferation. Furthermore, inhibition of cyclin A1 in Six1-overexpressing mammary carcinoma cells decreases proliferation. Together these results demonstrate that cyclin A1 is required for the proliferative effect of Six1. We conclude that Six1 overexpression reinstates an embryonic pathway of proliferation in breast cancer by up-regulating cyclin A1.

Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

“…The multiple mechanisms of Six1 regulation throughout the cell cycle suggest that it is critical to confine the activity of this transcription factor to specific cell cycle stages, where it is expected to play an important role. Indeed, our previous studies in tissue culture cells have demonstrated that Six1 overexpression can alter progression through S phase and also through G 2 /M (Ford et al, 1998;Coletta et al, 2004), times when Six1 activity would be expected to be high. Furthermore, a number of knockout studies in mice have demonstrated a critical role for Six1 in the proliferation of precursor cell populations, leaving no ambiguity about the importance of Six1 in proliferation in vivo (Zheng et al, 2003;Ozaki et al, 2004).…”

“…We have previously shown that Six1 promotes cell cycle progression (Ford et al, 1998;Coletta et al, 2004), and that Six1 transcript levels and phosphorylation state are regulated in the cell cycle (Ford et al, 1998(Ford et al, , 2000. As the expression of many proteins with cell cycle regulatory functions is controlled by ubiquitin-mediated proteolysis, we asked whether Six1 protein levels were also regulated in a cell cycle-specific manner.…”

“…(Li et al, 2003;Zheng et al, 2003;Ozaki et al, 2004). Gene amplification and overexpression of Six1 is observed in human cancers, where it confers developmental properties on adult cells leading to an increase in both proliferation and metastasis (Li et al, 2002;Coletta et al, 2004;Reichenberger et al, 2005;Yu et al, 2006). The pro-proliferative role of Six1 has been documented in both breast cancer and in rhabdomyosarcoma, although it has been most rigorously examined in breast cancer cells where it plays a role in entrance into and progression through S phase and in the G 2 cell cycle checkpoint (Ford et al, 1998;Coletta et al, 2004;Yu et al, 2006).…”

“…Gene amplification and overexpression of Six1 is observed in human cancers, where it confers developmental properties on adult cells leading to an increase in both proliferation and metastasis (Li et al, 2002;Coletta et al, 2004;Reichenberger et al, 2005;Yu et al, 2006). The pro-proliferative role of Six1 has been documented in both breast cancer and in rhabdomyosarcoma, although it has been most rigorously examined in breast cancer cells where it plays a role in entrance into and progression through S phase and in the G 2 cell cycle checkpoint (Ford et al, 1998;Coletta et al, 2004;Yu et al, 2006). Similar to many other genes that influence cellular proliferation, Six1 is itself regulated throughout the cell cycle both at the transcriptional level (Ford et al, 1998) and post-translationally through phosphorylation (Ford et al, 2000).…”

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

“…6,21 Besides, HDAC5 was reported to boost HCC cell proliferation through upregulation of Six1 which could activate cyclin A1. 22,23 In this study, we noticed that deprivation of HDAC5 impaired the hypoxia-induced migration and invasion of HCC cells; however, no obvious effect of HDAC5 knockdown was observed under normoxia. Meanwhile, HDAC5 overexpression enhanced the malignant phenotypes under hypoxia but not normoxia.…”