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Cytoplasmic Localization of RUNX3 via Histone Deacetylase-Mediated SRC Expression in Oxidative-Stressed Colon Cancer
Kyoung Ah Kang1, Mei Jing Piao1, Yea Seong Ryu1
1School of Medicine, Jeju National University, Jeju, Republic of Korea.
Abstract:
Runt domain transcription factor 3 (RUNX3) is a transcription factor that functions as a tumor suppressor. RUNX3 is frequently inactivated by epigenetic silencing or its protein mislocalization (cytoplasmic localization) in many cancer types. This study investigated whether oxidative stress induces redistribution of RUNX3 from the nucleus to the cytoplasm. The cytoplasmic localization of RUNX3 was associated with oxidative stress-induced RUNX3 phosphorylation at tyrosine residues via SRC activation. Moreover, oxidative stress increased expression of histone deacetylases (HDACs). RUNX3 phosphorylation and SRC expression induced by oxidative stress were inhibited by knockdown of HDAC1, restoring the nuclear localization of RUNX3 under oxidative stress. In conclusion, these results demonstrate that HDAC1- and SRC-mediated phosphorylation of RUNX3 induced by oxidative stress is associated with the cytoplasmic localization of RUNX3 and can lead to RUNX3 inactivation and carcinogenesis. J. Cell. Physiol. 232: 1914-1921, 2017. © 2016 Wiley Periodicals, Inc.
Insights
Oxidative stress causes tumor suppressor RUNX3 to move to the cytoplasm via HDAC1 and SRC activation. This redistribution inactivates RUNX3, promoting cancer development.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Runt domain transcription factor 3 (RUNX3) is a crucial tumor suppressor.
- RUNX3 inactivation occurs via epigenetic silencing or cytoplasmic mislocalization in cancers.
Purpose of the Study:
- To investigate if oxidative stress induces RUNX3 redistribution from the nucleus to the cytoplasm.
- To elucidate the molecular mechanisms underlying oxidative stress-induced RUNX3 mislocalization.
Main Methods:
- Assessing RUNX3 localization under oxidative stress conditions.
- Investigating the roles of SRC activation and histone deacetylases (HDACs) in RUNX3 phosphorylation and localization.
- Utilizing knockdown techniques for HDAC1 to observe effects on RUNX3.
Main Results:
- Oxidative stress induced RUNX3 phosphorylation at tyrosine residues, mediated by SRC activation.
- Increased expression of HDACs was observed under oxidative stress.
- Knockdown of HDAC1 inhibited oxidative stress-induced RUNX3 phosphorylation and SRC expression, restoring nuclear RUNX3 localization.
Conclusions:
- HDAC1 and SRC-mediated phosphorylation of RUNX3 by oxidative stress leads to its cytoplasmic localization.
- This mislocalization contributes to RUNX3 inactivation and subsequent carcinogenesis.
