Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

Abstract

Biomarkers for predicting chemotherapy response are important to treatment of colorectal cancer (CRC) patients. Cryptochrome 2 (CRY2) is a circadian clock protein involved in cell cycle, but the biological 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 CRC samples, and CRY2 overexpression is correlated with poor patient survival. Knockdown CRY2 increased colorectal cancer sensitivity to oxaliplatin in colorectal cancer cell. 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 CRY2’s turnover rate. High expressed FBXW7 downregulates CRY2 and increases colorectal cancer cells sensitivity to chemotherapy. Low FBXW7 expression is correlated with high CRY2 expression in CRC 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.

The intricate dance of post-translational modifications in the rhythm of life

“…In addition to FBXL3 and FBXL21, DNA-damage-binding protein 1 (DDB1) and FBXW7 E3 ligases have recently been reported to regulate degradation of CRY1 and CRY2, respectively 67,68 , thus further underscoring the complexity of CRY regulation. Similarly to PER ubiquitination, CRY degradation is also enhanced by phosphorylation.…”

“…Phosphorylation at Ser71 of CRY1 (corresponding to Ser89 of CRY2) by AMP-activated protein kinase recruits FBXL3 and promotes CRY degradation 69 . The FBXW7-containing SCF complex ubiquitinates CRY2 phosphorylated at Thr300 in the FBXW7 phosphodegron (300-TPPLS-304), thus leading to proteasomal degradation 68 . Ser557 in the unique C-terminal region of CRY2 (not conserved between CRY1 and CRY2) is phosphorylated by dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) 70 .…”

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

“…Circadian dysfunction is also thought to be a cancer risk factor in many organ systems (13)(14)(15)(16)(17)(18)(19). Aberration in circadian homeostasis is also linked to poor performance in antitumour regimes (17,20,21). Circadian dysregulation is widespread in cancer, yet, tumourspecific abnormalities of clock genes are far from being understood.…”

Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

“…The same mRNA transcript may be targeted by different miRNAs and a single miRNA, in turn, may target several different mRNAs [22]. Derangements in the miRNA-mRNA interactions [23], as well as altered expression of clock genes [24, 25] play a role in CRC onset and development and impact colon cancer cell behavior and response to chemotherapy [26, 27]. …”