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Volume 30, No 2, Feb 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 2, February 2020: 163-178   |  Open Access

ORIGINAL ARTICLES

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

Kai Li 1,2, Jian-lin Wu3, Baifu Qin 1,2, Zongmin Fan 1,2, Qin Tang 1,2, Weisi Lu4, Haipeng Zhang5, Fan Xing6, Manqi Meng 1,2, Shaomin Zou 1,2, Wenxia Wei 1,2, Honglei Chen7, Jian Cai7, Huaiming Wang7, Hui Zhang8, Jiayue Cai 1,2, Ling Fang 9, Xiqing Bian3, Chuangqi Chen 10, Ping Lan 1,2,7, Bart Ghesquière11, Lekun Fang 1,2,7 and Mong-Hong Lee 1,2

1 Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655 Guangzhou, China; 2Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655 Guangzhou, China; 3State 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; 4State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; 5Department of Pharmacology, School of Medicine, Jinan University, 510632 Guangzhou, China; 6School of Medicine, Sun Yat-sen University, Guangzhou, China; 7Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655 Guangzhou,China; 8Zhongshan School of Medicine, Sun Yat-sen University, 510080 Guangzhou, China; 9Instrumental Analysis & Research Center, Sun Yat-sen University, 510080 Guangzhou, China; 10Department of Colorectal Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510000 Guangzhou, China and 11Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, Belgium
 Correspondence: Lekun Fang (fanglk3@mail.sysu.edu.cn) or Mong-Hong Lee (limh33@mail.sysu.edu.cn)These authors contributed equally: Kai Li, Jian-lin Wu

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.


https://doi.org/10.1038/s41422-019-0257-1

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