Theranostics 2020; 10(13):5763-5777. doi:10.7150/thno.38087 This issue Cite

Research Paper

JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy

Juan Tan1*, Hao-Lian Wang1*, Jie Yang2, Qian-Qian Liu1, Chun-Min Li1, Yun-Qian Wang1, Lin-Na Fu1, Qin-Yan Gao1, Ying-Xuan Chen1✉, Jing-Yuan Fang1

1. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease;145 Middle Shandong Road, Shanghai 200001, China.
2. Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Education Ministry for Cell Differentiation and Apoptosis, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine. 280 South Chongqing Rd, Shanghai 200025, China.
* These authors contributed equally to this work.

Citation:
Tan J, Wang HL, Yang J, Liu QQ, Li CM, Wang YQ, Fu LN, Gao QY, Chen YX, Fang JY. JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy. Theranostics 2020; 10(13):5763-5777. doi:10.7150/thno.38087. https://www.thno.org/v10p5763.htm
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Abstract

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Rationale: Post-translational modifications have emerged as vital players in alterations to tumor metabolism, including amino acid metabolic reprogramming. Jumonji domain-containing protein 2B (JMJD2B) enhances colorectal cancer (CRC) cell survival upon glucose deficiency. In the present study, we hypothesized that JMJD2B affects tumor cell amino acid metabolism in CRC and consequently promotes survival of CRC cells upon glucose deprivation.

Methods: Non-target metabolic profiling was used to evaluate the roles of JMJD2B in CRC cell metabolism under glucose starvation. The roles of amino acid alterations induced by JMJD2B on CRC cell survival were determined by cell viability, immunoblotting, and clonogenic assays, and flow cytometry. The underlying mechanisms by which JMJD2B affected CRC cell metabolism were assessed using immunofluorescence staining, chromatin immunoprecipitation assays, electron microscopy in CRC cell lines, and using xenograft models. The correlation between JMJD2B and LC3B expression in human CRC specimens was assessed using immunohistochemistry.

Results: Profound metabolic reprogramming was detected in JMJD2B knockdown CRC cells under glucose deficiency, especially those involving amino acid metabolites. Silencing of JMJD2B reduced the levels of certain amino acids that were induced by glucose deficiency. Among these amino acids, asparagine (Asn), phenylalanine (Phe), and histidine (His) promoted CRC cell survival under glucose starvation when JMJD2B was knocked down. Mechanistically, downregulation of JMJD2B inhibited autophagy in CRC cells through epigenetic regulation of microtubule associated protein 1 light chain 3 beta (LC3B), and subsequently decreased intracellular amino acid (Asn, Phe, His) levels under glucose deprivation, thus suppressing the survival of CRC cells. Using a nude mouse xenograft model, we verified that inhibiting JMJD2B could decrease the levels of amino acids (Asn, Phe, His). In addition, the inhibitory effects of JMJD2B-knockdown on tumor growth and amino acids level were rescued by overexpression of LC3B. Furthermore, we observed that the high expression of LC3B was more likely detected in tissuses with high expression of JMJD2B (P < 0.001) in 60 human CRC tissues.

Conclusion: These results indicated that JMJD2B sustained the intracellular amino acids derived from autophagy in CRC cells upon glucose deficiency, partly through epigenetic regulation of LC3B, thus driving the malignancy of CRC.

Keywords: JMJD2B, CRC, amino acids metabolism, autophagy, LC3B


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APA
Tan, J., Wang, H.L., Yang, J., Liu, Q.Q., Li, C.M., Wang, Y.Q., Fu, L.N., Gao, Q.Y., Chen, Y.X., Fang, J.Y. (2020). JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy. Theranostics, 10(13), 5763-5777. https://doi.org/10.7150/thno.38087.

ACS
Tan, J.; Wang, H.L.; Yang, J.; Liu, Q.Q.; Li, C.M.; Wang, Y.Q.; Fu, L.N.; Gao, Q.Y.; Chen, Y.X.; Fang, J.Y. JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy. Theranostics 2020, 10 (13), 5763-5777. DOI: 10.7150/thno.38087.

NLM
Tan J, Wang HL, Yang J, Liu QQ, Li CM, Wang YQ, Fu LN, Gao QY, Chen YX, Fang JY. JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy. Theranostics 2020; 10(13):5763-5777. doi:10.7150/thno.38087. https://www.thno.org/v10p5763.htm

CSE
Tan J, Wang HL, Yang J, Liu QQ, Li CM, Wang YQ, Fu LN, Gao QY, Chen YX, Fang JY. 2020. JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy. Theranostics. 10(13):5763-5777.

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