CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression

Exp Hematol Oncol. 2023 Sep 7;12(1):77. doi: 10.1186/s40164-023-00440-z.

Dakui Luo ^# ¹ ², Min Chen ^# ³ ⁴, Qingguo Li ^# ¹ ², Kangjunjie Wang ³ ⁵, Kaihua Wang ³ ⁴, Junqiang Li ⁶, Guoxiang Fu ⁶, Zezhi Shan ¹ ², Qi Liu ¹ ², Yufei Yang ¹ ², Lei Liang ¹ ², Yanlei Ma ¹ ², Yi Qin ² ⁷, Jun Qin ⁸, Daming Gao ⁹ ¹⁰ ¹¹, Xinxiang Li ¹² ¹³

Affiliations

1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
3 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
4 University of Chinese Academy of Sciences, Beijing, 100049, China.
5 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
6 D1 Medical Technology (Shanghai) Co., Ltd, Shanghai, 201802, China.
7 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
8 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
9 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].
10 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
11 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. [email protected].
12 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
13 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
# Contributed equally.

PMID: 37679762 DOI: 10.1186/s40164-023-00440-z

Abstract

Background: UTX (encoded by KDM6A), a Histone Demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal Cancer (CRC) remain unclear.

Methods: Immunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses.

Results: Herein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of Histone Methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 Ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression.

Conclusions: In the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.

Keywords

COP1; Colorectal cancer; UTX; Ubiquitylation.

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