title: Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer.
abstract: Biomarkers for predicting chemotherapy response are important to the treatment of colorectal cancer patients. Cryptochrome 2 (CRY2) is a circadian clock protein involved in cell cycle, but the biologic consequences of this activity in cancer are poorly understood. We set up biochemical and cell biology analyses to analyze CRY2 expression and chemoresistance. Here, we report that CRY2 is overexpressed in chemoresistant colorectal cancer samples, and CRY2 overexpression is correlated with poor patient survival. Knockdown of CRY2 increased colorectal cancer sensitivity to oxaliplatin in colorectal cancer cells. We also identify FBXW7 as a novel E3 ubiquitin ligase for targeting CRY2 through proteasomal degradation. Mechanistic studies show that CRY2 is regulated by FBXW7, in which FBXW7 binds directly to phosphorylated Thr300 of CRY2. Furthermore, FBXW7 expression leads to degradation of CRY2 through enhancing CRY2 ubiquitination and accelerating the CRY2's turnover rate. High FBXW7 expression downregulates CRY2 and increases colorectal cancer cells' sensitivity to chemotherapy. Low FBXW7 expression is correlated with high CRY2 expression in colorectal cancer patient samples. Also, low FBXW7 expression is correlated with poor patient survival. Taken together, our findings indicate that the upregulation of CRY2 caused by downregulation of FBXW7 may be a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.
authors: Department of Surgery, Guangdong Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lekun
authors: L
authors: Fang
authors: Department of Surgery, Guangdong Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors: Zihuan
authors: Z
authors: Yang
authors: Department of Surgery, Guangdong Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors: Junyi
authors: J
authors: Zhou
authors: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors: Jung-Yu
authors: JY
authors: Tung
authors: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors: Chwan-Deng
authors: CD
authors: Hsiao
authors: Department of Surgery, Guangdong Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors: Lei
authors: L
authors: Wang
authors: Department of Oncology, Guangdong Gastroenterology Institute, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors: Yanhong
authors: Y
authors: Deng
authors: Department of Surgery, Guangdong Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors: Puning
authors: P
authors: Wang
authors: Department of Surgery, Guangdong Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. wangjpgz@163.com mhlee@mdanderson.org.
authors: Jianping
authors: J
authors: Wang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. wangjpgz@163.com mhlee@mdanderson.org.
authors: Mong-Hong
authors: MH
authors: Lee
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C538966:CRY2 protein, human; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D044767:Ubiquitin-Protein Ligases; D002955:Leucovorin; D005472:Fluorouracil