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Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis.

F Zhang¹, D M Virshup^1,2,3, J K Cheong¹

¹Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.

|September 26, 2017

Summary

This summary is machine-generated.

Cancer cells evade growth suppression by eliminating FOXO (forkhead box O) tumor suppressors. This study reveals Casein Kinase 1 alpha (CK1α) and proteasome-mediated degradation of FOXO4 in RAS-mutant cancers, offering new therapeutic targets.

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Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

Evasion of forkhead box O (FOXO) transcription factor-mediated growth suppression is crucial for cancer development.
FOXO gene alterations are infrequent in human cancers, suggesting post-translational mechanisms for their elimination.
Casein Kinase 1 alpha (CK1α) regulates FOXO3A stability in an oncogenic RAS-specific manner, but its effect on other FOXO members is unknown.

Purpose of the Study:

To investigate if CK1α destabilizes FOXO4 in RAS-mutant cells.
To elucidate the role of oncogenic RAS signaling in FOXO4 degradation.
To evaluate the therapeutic potential of targeting CK1α and the proteasome in RAS-mutant cancers.

Main Methods:

Phosphorylation site mapping of FOXO4.
Analysis of PI3K/AKT signaling pathway activation.
Assessment of proteasome subunit expression and activity.
Cell viability assays and apoptosis induction studies following dual inhibition of CK1α and proteasome.

Main Results:

CK1α destabilizes FOXO4 in RAS-mutant cells via phosphorylation at serines 265/268.
Oncogenic RAS signaling, partly through PI3K/AKT, primes FOXO4 for CK1α-dependent degradation.
Mutant RAS upregulates proteasome activity to degrade nuclear FOXO4.
Dual inhibition of CK1α and proteasome synergistically reduces RAS-mutant cancer cell growth by blocking FOXO4 degradation and inducing apoptosis.

Conclusions:

CK1α and proteasome-mediated degradation, not nuclear export, eliminates FOXO4 tumor suppressors in RAS-mutant cancers.
Oncogenic RAS utilizes post-translational mechanisms to degrade FOXO proteins, thereby promoting cancer.
Targeting CK1α and the proteasome simultaneously presents a promising therapeutic strategy for RAS-mutant cancers.