MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance
Authors: Shan Zhou
Yuejin Li
Chaojun Duan
Tiebang Kang
Jinping Lu
Faqing Tang
Yuanzhong Wu
Zigang Dong
Journal: Theranostics (2018)
Discipline: CLINICAL MEDICINE
Keywords: MICAL2; colorectal cancer; oxidation; p53; tumorigenesis
Affiliations: Department of Clinical Laboratory, Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013, Changsha, China., Department of Clinical Laboratory and Medical Research Center, Zhuhai Hospital, Jinan University, Zhuhai 519000, Guangdong, China., State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China., Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912.

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. 

Retracted: Yes

PubPeer comments:
 Figure 1 has four images which appear in multiple articles. This is part of a larger group of articles with overlapping authors, which has numerous duplicated pictures. I could also not help but noticing that the black boxes marking what region has been magnified are wrong. I marked the two most obvious cases. ![file] MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance, Theranostics. 2018; 8(19):5289--5306., doi:u00a010.7150 thno.28228, Figure 1 ![file] MNAT1 is overexpressed in colorectal cancer and mediates p53 ubiquitindegradation to promote colorectal cancer malignance, J Exp Clin Cancer Res. 2018; 37:284. doi:u00a010.1186 s13046-018-0956-3, Figure 1 ![file] Nuclear factor-erythroid 2-related factor 3 (NRF3) is low expressed in colorectal cancer and its down-regulation promotes colorectal cancer malignance through activating EGFR and p38 MAPK, Am J Cancer Res. 2019; 9(3): 511--528, PMID: 30949407, Figure 1 ![file] Nuclear factor-erythroid 2-related factor 3 (NRF3) is low expressed in colorectal cancer and its down-regulation promotes colorectal cancer malignance through activating EGFR and p38 MAPK, Am J Cancer Res. 2019; 9(3): 511--528, PMID: 30949407, Figure 3 , 
 The tumors in Figure 5C also appears in a second article with overlapping authors. There are no references between the two articles. Notice the difference in the ruler at the bottom of the picture. A close-up with higher contrast reveals that it is the picture in the second article that has been altered. ![file] MICAL2 Mediates p53 Ubiquitin Degradation through Oxidating p53 Methionine 40 and 160 and Promotes Colorectal Cancer Malignance, Theranostics. 2018; 8(19):5289--5306., doi:u00a010.7150 thno.28228, Figure 5C ![file] Nuclear factor-erythroid 2-related factor 3 (NRF3) is low expressed in colorectal cancer and its down-regulation promotes colorectal cancer malignance through activating EGFR and p38 MAPK, Am J Cancer Res. 2019; 9(3): 511--528, PMID:u00a030949407, Figure 7D Below is a close-up of the bottom right corner form the first picture. ![file] , 
 Much more similar than expect between Fig 2H and 4E ![file] , 
 Itu2019s good that this article has been retracted for image reuse. In addition, the cutting edge journal Theranostics might want to review the ethics training of their editors. Some of the xenografts in Fig. 5A are way too large ( 2 cm diameter), notably for the control mouse at the top left. One hopes these mice have not appeared in any other publications. ![image] ,