CASZ1b, the short isoform of CASZ1 gene, coexpresses with CASZ1a during neurogenesis and suppresses neuroblastoma cell growth.

Abstract

In Drosophila, the CASZ1 (castor) gene encodes a zinc finger transcription factor and is a neural fate-determination gene. In mammals, the CASZ1 gene encodes two major isoforms, CASZ1a with 11 zinc fingers and CASZ1b with 5 zinc fingers. CASZ1b is more evolutionally conserved since it is the only homologue found in drosophila and Xenopus. Our previous study showed that full length CASZ1 (CASZ1a) functions to suppress growth in neuroblastoma tumor. However, the function of CASZ1b isoform in mammals is unknown. In this study, realtime PCR analyses indicate that mouse CASZ1b (mCASZ1b) is dynamically expressed during neurogenesis. CASZ1b and CASZ1a co-exist in all the neuronal tissues but exhibit distinct expression patterns spatially and temporally during brain development. CASZ1b and CASZ1a expression is coordinately upregulated by the differentiation agent Retinoic Acid, as well as agents that modify the epigenome in neural crest derived neuroblastoma cell lines. In contrast CASZ1b is down regulated while CASZ1a is upregulated by agents that raise intracellular cAMP levels. CASZ1b and CASZ1a have no synergistic or antagonistic activities on the regulation of their target NGFR gene transcription. Specific restoration of CASZ1b in NB cells suppresses tumor growth in vitro and in vivo. Consistent with its function role, we find that low CASZ1b expression is significantly associated with decreased survival probability of neuroblastoma patients (p<0.02). This study indicates that although their mechanisms of regulation may be distinct, both CASZ1b and CASZ1a have largely redundant but critical roles in suppressing tumor cell growth.