CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1

Oncogene. 2022 Sep;41(39):4433-4445. doi: 10.1038/s41388-022-02439-y.

Han Ling ^# ¹, Chen-Hui Cao ^# ¹ ², Kai Han ^# ¹ ³, Yong-Rui Lv ^# ¹, Xiao-Dan Ma ¹, Jing-Hua Cao ¹, Jie-Wei Chen ¹ ⁴, Si Li ¹, Jin-Long Lin ¹, Yu-Jing Fang ¹ ³, Zhi-Zhong Pan ¹ ³, Dan Xie ⁵ ⁶, Feng-Wei Wang ⁷

Affiliations

1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
2 Integrative Cancer Center & Cancer Clinical Research Center, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.
3 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
4 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
5 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China. xiedan@sysucc.org.cn.
6 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. xiedan@sysucc.org.cn.
7 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China. wangfengw@sysucc.org.cn.
# Contributed equally.

PMID: 35989368 DOI: 10.1038/s41388-022-02439-y

Abstract

Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in Cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal Cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal Cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote Cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.

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