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.
Highlights
Colorectal cancer (CRC), including the carcinogenesis of colon and rectal, is an important contributor to cancer mortality and morbidity.[1,2] there is an urgent need to identify risk factors, biomarkers, and effective treatment strategies for CRC
We show that the frequent overexpression of Interleukin enhancer-binding factor 3 (ILF3) in CRC results in the metabolic reprogramming phenotype in serine biosynthesis that promotes tumor growth, organoid formation, and correlates with poor cancer survival
ILF3 is overexpressed in CRC and is a prognostic marker correlated with poor survival To identify potential deregulated genes in CRC tumorigenesis, we examined the microarray gene expression profile of colorectal cancer tissues from patients with newly diagnosed CRC versus adjacent normal tissues
Summary
Colorectal cancer (CRC), including the carcinogenesis of colon and rectal, is an important contributor to cancer mortality and morbidity.[1,2] there is an urgent need to identify risk factors, biomarkers, and effective treatment strategies for CRC. Deregulation of cellular energetics (metabolic reprogramming), one of the cancer hallmarks, involves tumor cells to rewire metabolic pathways to support rapid proliferation, continuous growth, metastasis, and resistance to therapies.[5,6] Serine biosynthesis supports several metabolic processes that are crucial for the growth and survival of proliferating cells.[7,8,9] For examples, loss of LKB1 tumor suppressor leads to activation of serine biosynthesis to support tumor growth and DNA methylation.[10] K-ras-driven pancreatic and intestinal cancers are less responsive to serine/ glycine depletion-mediated cancer inhibition.[11] Genes involved in the serine synthesis pathway, including PHGDH, PSAT1, PSPH, SHMT1 and SHMT2, are deregulated in several cancers These genes encode enzymes to produce serine and glycine from glycolytic intermediate 3-phosphoglycerate. Phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the SGOC pathway, is amplified in breast cancer and melanomas.[12,13] NRF2 and Myc activate the expression of genes in serine synthesis pathway in cancer.[14,15] HER2 and p53 regulate the expression of PHGDH.[9]
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