Abstract
Previously, we reported that ZNF300 might play a role in leukemogenesis. In this study, we further investigated the function of ZNF300 in K562 cells undergoing differentiation. We found that ZNF300 upregulation in K562 cells coincided with megakaryocytic differentiation induced by phorbol-12-myristate-13-acetate (PMA) or erythrocytic differentiation induced by cytosine arabinoside (Ara-C), respectively. To further test whether ZNF300 upregulation promoted differentiation, we knocked down ZNF300 and found that ZNF300 knockdown effectively abolished PMA-induced megakaryocytic differentiation, evidenced by decreased CD61 expression. Furthermore, Ara-C-induced erythrocytic differentiation was also suppressed in ZNF300 knockdown cells with decreased γ-globin expression and CD235a expression. These observations suggest that ZNF300 may be a critical factor controlling distinct aspects of K562 cells. Indeed, ZNF300 knockdown led to increased cell proliferation. Consistently, ZNF300 knockdown cells exhibited an increased percentage of cells at S phase accompanied by decreased percentage of cells at G0/G1 and G2/M phase. Increased cell proliferation was further supported by the increased expression of cell proliferation marker PCNA and the decreased expression of cell cycle regulator p15 and p27. In addition, MAPK/ERK signaling was significantly suppressed by ZNF300 knockdown. These findings suggest a potential mechanism by which ZNF300 knockdown may impair megakaryocytic and erythrocytic differentiation.
Highlights
Kruppel-associated box (KRAB)-containing zinc finger proteins (ZFPs) comprise a large family of transcription regulators in mammals
We demonstrated that ZNF300 was upregulated in K562 cells undergoing megakaryocytic differentiation induced by PMA or erythrocytic differentiation induced by Ara-C, respectively
Our study suggests a novel function of ZNF300 in megakaryocytic and erythrocytic differentiation
Summary
Kruppel-associated box (KRAB)-containing zinc finger proteins (ZFPs) comprise a large family of transcription regulators in mammals. KRAB-ZFPs typically bear an N-terminal KRAB (Kruppel-associated box) domain that functions to suppress transcription by recruiting KRAB domain-associated protein 1 (KAP-1). KAP1 subsequently recruits histone deacetylase and histone methyltransferase machinery to mediate heterochromatinization and gene silencing [1,2,3,4,5,6,7]. Based on the structure of the KRAB domain, the KRAB-ZFPs can be further classified into three subfamilies: KRAB (AB) with a classical A-box and a B-box, KRAB (A) with a classical A-box only, and KRAB (Ab) with a classical A-box and a highly divergent B-box [8]. The A-box is highly conserved and plays a key role in the repression of target genes while the B-box is less conserved and plays an auxiliary role [9]. It’s been reported that the KRAB-ZFPs are only found in the tetrapod vertebrate, suggesting an important function of KRAB-ZFPs in the evolution process of the higher organisms [10, 11]
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