Identification and characterization of the CDK1-BMAL1-UHRF1 pathway driving tumor progression

Dan Wang; Fenglin Wang; Shengfeng Wang; Ling Chu; Daolin Tang; Pan Chen; Minghua Yang

doi:10.1016/j.isci.2023.106544

Identification and characterization of the CDK1-BMAL1-UHRF1 pathway driving tumor progression

iScience. 2023 Mar 31;26(4):106544. doi: 10.1016/j.isci.2023.106544. eCollection 2023 Apr 21.

Authors

Dan Wang^{1

2}, Fenglin Wang^{1

2}, Shengfeng Wang³, Ling Chu⁴, Daolin Tang⁵, Pan Chen⁶, Minghua Yang^{1

2}

Affiliations

¹ Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
² Hunan Clinical Research Center of Pediatric Cancer, Changsha, Hunan 410013, China.
³ Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
⁴ Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
⁵ Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410031, China.

Abstract

The abnormal regulation of BMAL1 could lead to the occurrence and progression of various tumors. However, the mechanism of phosphorylation regulation of BMAL1 in tumorigenesis remains poorly understood. In this study, we report a previously unrecognized BMAL1 dephosphorylation pathway that promotes tumor progression. BMAL1 accelerates cell proliferation, migration, and invasion of HT1080 and Calu1 cells. CDK1 binds to BMAL1 through a conserved domain and regulates the dephosphorylation of BMAL1 on Ser42 residues, but not on Ser78 or Thr224, thereby enhancing the oncogenic activity of BMAL1. Dephosphorylation of BMAL1 Ser42 promotes tumor growth and metastasis in mouse subcutaneous transplantation tumor and lung metastatic tumor models. Moreover, UHRF1 is recognized as an important target gene of BMAL1 in cancer cells. Consequently, UHRF1 depletion mimics BMAL1 deficiency with respect to tumor suppression, whereas transfection-enforced re-expression of UHRF1 restores tumor growth in BMAL1-deficient cells. These findings suggest a link between the circadian clock regulator and cancer progression.

Keywords: Cancer; Cell biology; Molecular biology.