Targeting posttranslational modifications of RioK1 inhibits the progression of colorectal and gastric cancers

AbstractRioK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RioK1 is methylated at K411 by SETD7 methyltransferase, and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RioK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RioK1. FBXO6 specifically interacts with K411-methylated RioK1 through its FBA domain to induce RioK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RioK1 at T410, which stabilizes RioK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RioK1. Functional experiments demonstrate the RioK1 methylation reduces the tumor growth and metastasis in CRC and GC. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human CRC tissues. Therefore, this study highlights the importance of a RioK1 methylation-phosphorylation switch in determining CRC and GC development.

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Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers

eLife ◽

10.7554/elife.29511 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 12

Author(s):

Xuehui Hong ◽

He Huang ◽

Xingfeng Qiu ◽

Zhijie Ding ◽

Xing Feng ◽

...

Keyword(s):

Posttranslational Modifications ◽

Inverse Correlation ◽

Cancer Development ◽

Posttranslational Regulation ◽

Mice Model ◽

Human Colorectal Cancer ◽

Protein Levels ◽

Lysine Specific Demethylase ◽

Tumor Growth And Metastasis ◽

Cancer Tissues

RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1. Functional experiments demonstrate the RIOK1 methylation reduces the tumor growth and metastasis in mice model. Importantly, the protein levels of CK2 and LSD1 show an inverse correlation with FBXO6 and SETD7 expression in human colorectal cancer tissues. Together, this study highlights the importance of a RIOK1 methylation-phosphorylation switch in determining colorectal and gastric cancer development.

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Casein Kinase 2–Interacting Protein-1, a Novel Akt Pleckstrin Homology Domain-Interacting Protein, Down-regulates PI3K/Akt Signaling and Suppresses Tumor Growth In vivo

Cancer Research ◽

10.1158/0008-5472.can-07-1050 ◽

2007 ◽

Vol 67 (20) ◽

pp. 9666-9676 ◽

Cited By ~ 47

Author(s):

Emi Tokuda ◽

Naoya Fujita ◽

Tomoko Oh-hara ◽

Shigeo Sato ◽

Atsuo Kurata ◽

...

Keyword(s):

Tumor Growth ◽

Akt Signaling ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Pleckstrin Homology Domain ◽

Pleckstrin Homology ◽

Interacting Protein

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ROCK2-Specific Inhibitor KD025 Suppresses Adipocyte Differentiation by Inhibiting Casein Kinase 2

Molecules ◽

10.3390/molecules26164747 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4747

Author(s):

Nhu Nguyen Quynh Tran ◽

Kwang-Hoon Chun

Keyword(s):

Lipid Droplets ◽

Adipocyte Differentiation ◽

Specific Inhibitor ◽

Inhibitory Effect ◽

Cross Reactivity ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Rock Inhibitor ◽

Protein Levels ◽

Screening Platform

KD025, a ROCK2 isoform-specific inhibitor, has an anti-adipogenic activity which is not mediated by ROCK2 inhibition. To identify the target, we searched binding targets of KD025 by using the KINOMEscanTM screening platform, and we identified casein kinase 2 (CK2) as a novel target. KD025 showed comparable binding affinity to CK2α (Kd = 128 nM). By contrast, CK2 inhibitor CX-4945 and ROCK inhibitor fasudil did not show such cross-reactivity. In addition, KD025 effectively inhibited CK2 at a nanomolar concentration (IC50 = 50 nM). We examined if the inhibitory effect of KD025 on adipocyte differentiation is through the inhibition of CK2. Both CX-4945 and KD025 suppressed the generation of lipid droplets and the expression of proadipogenic genes Pparg and Cebpa in 3T3-L1 cells during adipocyte differentiation. Fasudil exerted no significant effect on the quantity of lipid droplets, but another ROCK inhibitor Y-27632 increased the expression of Pparg and Cebpa. Both CX-4945 and KD025 acted specifically in the middle stage (days 1–3) but were ineffective when treated at days 0–1 or the late stages, indicating that CX-4945 and KD025 may regulate the same target, CK2. The mRNA and protein levels of CK2α and CK2β generally decreased in 3T3-L1 cells at day 2 but recovered thereafter. Other well-known CK2 inhibitors DMAT and quinalizarin inhibited effectively the differentiation of 3T3-L1 cells. Taken together, the results of this study confirmed that KD025 inhibits ROCK2 and CK2, and that the inhibitory effect on adipocyte differentiation is through the inhibition of CK2.

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