Page 8 - T. Protein modification and regulation

[T. Protein modification and regulation-4]

Regulation of Fra-1 protein stability through deubiquitination

promotes colorectal cancer metastasis

Sun-Il Yun¹, Kyeong Kyu Kim¹˙*

¹Precision Medicine, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea, ²Health

Science and Technology, Samsung Advanced Institute for Health Science and Technology, Seoul 06531, Republic
of Korea

Fos-related-antigen-1 (Fra-1), a member of the activator protein-1 (AP-1) transcription factor superfamily, has an

essential role in cancer progress and metastasis and Fra-1 is considered a therapeutic target in metastatic cancer

including metastatic colorectal cancer (mCRC). However, its regulation at protein level has not yet been clearly
elucidated. We found that DUB increases Fra-1 stability by its protein deubiquitination and enhances the target
gene expression of Fra-1 in colon cancer cells. We also showed that DUB positively controlled Fra-1-dependent

migration and invasion activities. The oncogenic property of DUB was confirmed by a significant reduction in liver
metastasis when DUB-knockdown cells were injected intra-splenically into mice. Consistently, clinico-pathological

analysis of colorectal cancer patients revealed the correlation of USP21 expression with high-grade carcinoma and
life span. This study demonstrated that DUB enhances Fra-1 stability and AP-1 target gene expression by

deubiquitinating Fra-1. Therefore, DUB in mCRC could be an attractive therapeutic target linked to high Fra-1
expression.