Theranostics 2018; 8(19):5289-5306. doi:10.7150/thno.28228 This issue Cite

Research Paper

MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance

Jinping Lu1,3*, Yuejin Li1*, Yuanzhong Wu2,*, Shan Zhou1, Chaojun Duan1, Zigang Dong4, Tiebang Kang2✉, Faqing Tang1,3✉

1. Department of Clinical Laboratory, Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013, Changsha, China
2. State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
3. Department of Clinical Laboratory and Medical Research Center, Zhuhai Hospital, Jinan University, Zhuhai 519000, Guangdong, China
4. Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912
*Lu J, Li Y, and Wu Y contributed equally to this work.

Citation:
Lu J, Li Y, Wu Y, Zhou S, Duan C, Dong Z, Kang T, Tang F. MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance. Theranostics 2018; 8(19):5289-5306. doi:10.7150/thno.28228. https://www.thno.org/v08p5289.htm
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Abstract

Graphic abstract

Molecule interacting with CasL2 (MICAL2), a microtubule-associated monooxygenase, is highly expressed in various cancers and is involved in cancer pathogenesis, but the mechanisms underlying its regulation in carcinogenesis are unclear. In this study, we aim to clarify the mechanism by which MICAL2 participates in colorectal cancer (CRC) and identify novel markers for predicting prognosis of CRC patients.

Methods: The value of MICAL2 in CRC prognosis was determined by immunohistochemical analysis of a CRC biopsy array. A short hairpin RNA target MICAL2 (shMICAL2) was designed to knock down MICAL2 expression and observe MICAL2's function on CRC cell growth. mRNA expression array was used to screen target molecules of MICAL2. HCT116 p53+/+ and HCT116 p53-/- cells were used to confirm whether MICAL2 exerts its oncogenic effect through p53. The in vivo effect of MICAL2 on CRC growth was assessed by subcutaneously injecting MICAL2-knockout CRC cells into the dorsal flank of each mouse. Immunofluorescence was used to observe the effect of MICAL2 on p53 cellular location. Reverse-phase nano ESI-LCMS analysis was used to investigate if MICAL2 mediates p53 oxidation.

Results: MICAL2 was found to be highly expressed in CRC tissues, and its expression was associated with CRC carcinogenesis and poor patient outcome. MICAL2-knockdown decreased growth and colony formation of CRC cells, which was linked with cell cycle arrest and apoptosis. MICAL2 physically interacted with p53 and retained p53 in the cytoplasm. MICAL2 shortened the half-life of p53, and ectopic MICAL2 expression decreased p53 protein stability through ubiquitin degradation. MICAL2 was also found to oxidize p53 at methionine 40 and 160, which mediated p53 ubiquitin degradation. MICAL2-promoted CRC growth in vivo was confirmed in nude mice.

Conclusion: MICAL2 binds to p53, retains p53 in the cytoplasm and oxidizes it at Met 40 and 160, promotes p53 ubiquitination, and decreases p53 function. MICAL2-reduced p53 promotes CRC development.

Keywords: MICAL2, colorectal cancer, p53, oxidation, ubiquitin, tumorigenesis


Citation styles

APA
Lu, J., Li, Y., Wu, Y., Zhou, S., Duan, C., Dong, Z., Kang, T., Tang, F. (2018). MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance. Theranostics, 8(19), 5289-5306. https://doi.org/10.7150/thno.28228.

ACS
Lu, J.; Li, Y.; Wu, Y.; Zhou, S.; Duan, C.; Dong, Z.; Kang, T.; Tang, F. MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance. Theranostics 2018, 8 (19), 5289-5306. DOI: 10.7150/thno.28228.

NLM
Lu J, Li Y, Wu Y, Zhou S, Duan C, Dong Z, Kang T, Tang F. MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance. Theranostics 2018; 8(19):5289-5306. doi:10.7150/thno.28228. https://www.thno.org/v08p5289.htm

CSE
Lu J, Li Y, Wu Y, Zhou S, Duan C, Dong Z, Kang T, Tang F. 2018. MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance. Theranostics. 8(19):5289-5306.

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