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Cell Res. 2019 Nov 26. doi: 10.1038/s41422-019-0257-1. [Epub ahead of print]

ILF3 is a substrate of SPOP for regulating serine biosynthesis in colorectal cancer.

Li K1,2, Wu JL3, Qin B1,2, Fan Z1,2, Tang Q1,2, Lu W4, Zhang H5, Xing F6, Meng M1,2, Zou S1,2, Wei W1,2, Chen H7, Cai J7, Wang H7, Zhang H8, Cai J1,2, Fang L9, Bian X3, Chen C10, Lan P1,2,7, Ghesquière B11, Fang L12,13,14, Lee MH15,16.

Author information

1
Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China.
2
Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China.
3
State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, China.
4
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
5
Department of Pharmacology, School of Medicine, Jinan University, 510632, Guangzhou, China.
6
School of Medicine, Sun Yat-sen University, Guangzhou, China.
7
Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China.
8
Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, China.
9
Instrumental Analysis & Research Center, Sun Yat-sen University, 510080, Guangzhou, China.
10
Department of Colorectal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, China.
11
Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, Belgium.
12
Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China. fanglk3@mail.sysu.edu.cn.
13
Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China. fanglk3@mail.sysu.edu.cn.
14
Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China. fanglk3@mail.sysu.edu.cn.
15
Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China. limh33@mail.sysu.edu.cn.
16
Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655, Guangzhou, China. limh33@mail.sysu.edu.cn.

Abstract

The Serine-Glycine-One-Carbon (SGOC) pathway is pivotal in multiple anabolic processes. Expression levels of SGOC genes are deregulated under tumorigenic conditions, suggesting participation of oncogenes in deregulating the SGOC biosynthetic pathway. However, the underlying mechanism remains elusive. Here, we identified that Interleukin enhancer-binding factor 3 (ILF3) is overexpressed in primary CRC patient specimens and correlates with poor prognosis. ILF3 is critical in regulating the SGOC pathway by directly regulating the mRNA stability of SGOC genes, thereby increasing SGOC genes expression and facilitating tumor growth. Mechanistic studies showed that the EGF-MEK-ERK pathway mediates ILF3 phosphorylation, which hinders E3 ligase speckle-type POZ protein (SPOP)-mediated poly-ubiquitination and degradation of ILF3. Significantly, combination of SGOC inhibitor and the anti-EGFR monoclonal antibody cetuximab can hinder the growth of patient-derived xenografts that sustain high ERK-ILF3 levels. Taken together, deregulation of ILF3 via the EGF-ERK signaling plays an important role in systemic serine metabolic reprogramming and confers a predilection toward CRC development. Our findings indicate that clinical evaluation of SGOC inhibitor is warranted for CRC patients with ILF3 overexpression.

PMID:
31772275
DOI:
10.1038/s41422-019-0257-1

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