PCGF2 negatively regulates arsenic trioxide-induced PML-RARA protein degradation via UBE2I inhibition in NB4 cells
- Authors
- Jo, Sungsin; Lee, Young Lim; Kim, Sojin; Lee, Hongki; Chung, Heekyoung
- Issue Date
- Jul-2016
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Arsenic trioxide; PCGF2; UBE2I; PML-RARA; Protein degradation; Sumoylation
- Citation
- BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v.1863, no.7, pp.1499 - 1509
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
- Volume
- 1863
- Number
- 7
- Start Page
- 1499
- End Page
- 1509
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/154306
- DOI
- 10.1016/j.bbamcr.2016.03.019
- ISSN
- 0167-4889
- Abstract
- Arsenic trioxide (ATO) is a therapeutic agent for acute promyelocytic leukemia (APL) which induces PML-RARA protein degradation via enhanced UBE2I-mediated sumoylation. PCGF2, a Polycomb group protein, has been suggested as an anti-SUMO E3 protein by inhibiting the sumoylation of UBE2I substrates, HSF2 and RANGAP1, via direct interaction. Thus, we hypothesized that PCGF2 might play a role in ATO-induced PML-RARA degradation by interacting with UBE2I. PCGF2 protein was down-regulated upon ATO treatment in human APL cell line, NB4. Knockdown of PCGF2 in NB4 cells, in the absence of ATO treatment, was sufficient to induce sumoylation-, ubiquitylation- and PML nuclear body-mediated degradation of PML-RARA protein. Moreover, overexpression of PCGF2 protected ATO-mediated degradation of ectopic and endogenous PML-RARA in 293T and NB4 cells, respectively. In 293T cells, UBE2I-mediated PML-RARA degradation was reduced upon PCGF2 co-expression. In addition, UBE2I-mediated sumoylation of PML-RARA was reduced upon PCGF2 co-expression and PCGF2-UBE2I interaction was confirmed by co-immunoprecipitation. Likewise, endogenous PCGF2-UBE2I interaction was detected by co-immunoprecipitation and immunofluorescence assays in NB4 cells. Intriguingly, upon ATO-treatment, such interaction was disrupted and UBE2I was co-immunoprecipitated or co-localized with its SUMO substrate, PML-RARA. Taken together, our results suggested a novel role of PCGF2 in ATO-mediated degradation of PML-RARA that PCGF2 might act as a negative regulator of UBE2I via direct interaction.
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