In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1971-1971
Abstract:
The promyelocytic leukemia (PML) protein elicits pleiotropic tumor suppressive functions and is aberrantly degraded in multiple types of human cancers through poorly understood mechanisms. Previous study in our laboratory revealed that CDK1/2-mediated phosphorylation of PML Ser518 is required for targeting PML to Pin1 for prolylisomerization and subsequently to KLHL20-containing ubiquitin ligase complex for ubiquitination and proteasomal degradation. To identify the negative regulators of this PML degradation pathway, we employed a functional genomic approach to search for phosphatases that act on PML Ser518. This study identifies the small C-terminal domain phosphatase 1/2/3 (SCP1/2/3) as PML Ser518 phosphatases. Because these three phosphatases are of structural and functional similarities, we focus on the prototype of this family, SCP1. We show that SCP1 interacts with PML and reduces PML Ser518 phosphorylation levels both in vivo and in vitro. Through this dephosphorylation, SCP1 decreases Pin1-KLHL20 mediated-PML polyubiquitination and prolongs PML half life. Consequently, SCP1 increases the number of PML-nuclear bodies and elevates PML protein abundance in both normoxia and hypoxia conditions. At functional levels, SCP1 overexpression enhances multiple tumor suppressive effects, including promotion of apoptosis and inhibition of cell proliferation and migration. Importantly, all of these effects are reversed by PML knockdown. Clinically, SCP1 expression is downregulated in renal clear cell carcinoma (RCC) and this downregulation correlates with PML downregulation. Restoration of SCP1-mediated PML stabilization inhibits RCC proliferation, migration and transformation. Together, our study identifies SCP1 as a positive regulator of PML by dephosphorylation of PML Ser518 to antagonize the Pin1/KLHL20-dependent PML degradation pathway. Blockage of SCP1/PML axis is manifested in RCC and contributes to RCC progression. Citation Format: Yu-Ching Lin, Li-Ting Lu, Xin-Hua Feng, Ruey-Hwa Chen. Small C-terminal domain phosphatase 1 stabilizes PML to regulate the progression of renal clear cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1971. doi:10.1158/1538-7445.AM2013-1971
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-1971
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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