Methionine adenosyltransferase α2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells

被引：4

作者：

Tomasi, Maria Lauda ^{[1
,2
]}

Ryoo, Minjung ^{[1
,2
]}

Ramani, Komal ^{[1
,2
]}

Tomasi, Ivan ^{[3
]}

Giordano, Pasquale ^{[4
]}

Mato, Jose M. ^{[5
]}

Lu, Shelly C. ^{[1
,2
]}

机构：

[1] Cedars Sinai Med Ctr, Div Gastroenterol, Los Angeles, CA 90048 USA

[2] Univ So Calif, Keck Sch Med, USC Res Ctr Liver Dis, Los Angeles, CA 90033 USA

[3] Rotherham Hosp, Dept Gen Surg, Rotherham S60 2UD, S Yorkshire, England

[4] Barts Hlth, Colorectal Dept, London E11 1NR, England

[5] Ctr Invest Biomed Red Enfermedades Hepat & Digest, CIC BioGUNE, Technol, Derio 48160, Bizkaia, Spain

来源：

ONCOTARGET | 2015年 / 6卷 / 35期

关键词：

methionine adenosyltransferase alpha 2; Bcl-2; ubiquitin-conjugating enzyme 9; sumoylation; colon cancer; HEPATOMA-CELLS; S-ADENOSYLMETHIONINE; COLORECTAL-CANCER; PROTEIN STABILITY; HEPG2; CELLS; SUMO; TRANSCRIPTION; PATHWAY; APOPTOSIS; 2A;

D O I：

暂无

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Ubiquitin-conjugating enzyme 9 (Ubc9) is required for sumoylation and inhibits apoptosis via Bcl-2 by unknown mechanism. Methionine adenosyltransferase 2A (MAT2A) encodes for MAT alpha 2, the catalytic subunit of the MATII isoenzyme that synthesizes S-adenosylmethionine (SAMe). Ubc9, Bcl-2 and MAT2A expression are up-regulated in several malignancies. Exogenous SAMe decreases Ubc9 and MAT2A expression and is pro-apoptotic in liver and colon cancer cells. Here we investigated whether there is interplay between Ubc9, MAT2A and Bcl-2. We used human colon and liver cancer cell lines RKO and HepG2, respectively, and confirmed key finding in colon cancer specimens. We found MAT alpha 2 can regulate Bcl-2 expression at multiple levels. MAT alpha 2 binds to Bcl-2 promoter to activate its transcription. This effect is independent of SAMe as MAT alpha 2 catalytic mutant was also effective. MAT alpha 2 also directly interacts with Bcl-2 to enhance its protein stability. MAT alpha 2's effect on Bcl-2 requires Ubc9 as MAT alpha 2's stability is influenced by sumoylation at K340, K372 and K394. Overexpressing wild type (but not less stable MAT alpha 2 sumoylation mutants) protected from 5-fluorouracil-induced apoptosis in both colon and liver cancer cells. Colon cancer have higher levels of sumoylated MAT alpha 2, total MAT alpha 2, Ubc9 and Bcl-2 and higher MAT alpha 2 binding to the Bcl-2 P2 promoter. Taken together, Ubc9's protective effect on apoptosis may be mediated at least in part by sumoylating and stabilizing MAT alpha 2 protein, which in turn positively maintains Bcl-2 expression. These interactions feed forward to further enhance growth and survival of the cancer cell.

引用

页码：37706 / 37723

页数：18

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