Reciprocal inhibition of PIN1 and APC/CCDH1 controls timely G1/S transition and creates therapeutic vulnerability

Shizhong Ke; Fabin Dang; Lin Wang; Jia-Yun Chen; Mandar T Naik; Abhishek Thavamani; Yansheng Liu; Wenxue Li; Nami Kim; Nandita M Naik; Huaxiu Sui; Wei Tang; Chenxi Qiu; Kazuhiro Koikawa; Felipe Batalini; Xiaodong Wang; John G Clohessy; Yujing Jan Heng; Galit Lahav; Nathanael S Gray; Xiao Zhen Zho; Wenyi Wei; Gerburg M Wulf; Kun Ping Lu

doi:10.21203/rs.3.rs-2447544/v1

Reciprocal inhibition of PIN1 and APC/C_CDH1 controls timely G1/S transition and creates therapeutic vulnerability

Res Sq [Preprint]. 2023 Jan 19:rs.3.rs-2447544. doi: 10.21203/rs.3.rs-2447544/v1.

Authors

Shizhong Ke^{1

2}, Fabin Dang^{3

2}, Lin Wang^{1

2}, Jia-Yun Chen^{4

5

2}, Mandar T Naik⁶, Abhishek Thavamani¹, Yansheng Liu^{7

8}, Wenxue Li⁷, Nami Kim¹, Nandita M Naik⁶, Huaxiu Sui⁹, Wei Tang¹⁰, Chenxi Qiu^{1

11}, Kazuhiro Koikawa¹, Felipe Batalini^{1

12}, Xiaodong Wang¹³, John G Clohessy¹⁴, Yujing Jan Heng³, Galit Lahav⁴, Nathanael S Gray¹⁵, Xiao Zhen Zho^{1

16}, Wenyi Wei³, Gerburg M Wulf¹, Kun Ping Lu^{1

16

17}

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
² These authors contributed equally to this work.
³ Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA 02215, USA.
⁴ Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA.
⁵ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
⁶ Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02912, USA.
⁷ Yale Cancer Biology Institute, West Haven, CT 06516, USA.
⁸ Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
⁹ Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen 361023, China.
¹⁰ Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, USA.
¹¹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Medicine, Division of Medical Oncology, Mayo Clinic, Arizona, USA.
¹³ Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
¹⁴ Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹⁵ Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
¹⁶ Departments of Biochemistry & Oncology, Schulich School of Medicine and Dentistry, and Robarts Research Institute, Western University, London, ON N6A 3K7, Canada.
¹⁷ Lead Contact.

Abstract

Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/C^CDH1), an E3 ubiquitin ligase that contains the co-activator CDH1, to promote G1/S transition. PIN1 is a phosphorylation-directed proline isomerase and a master cancer signaling regulator. However, little are known about APC/C^CDH1 regulation after phosphorylation and about PIN1 ubiquitin ligases. Here we uncover a domain-oriented reciprocal inhibition that controls the timely G1/S transition: The non-phosphorylated APC/C^CDH1 E3 ligase targets PIN1 for degradation in G1 phase, restraining G1/S transition; APC/C^CDH1 itself, after phosphorylation by CDKs, is inactivated by PIN1-catalyzed isomerization, promoting G1/S transition. In cancer, PIN1 overexpression and APC/C^CDH1 inactivation reinforce each other to promote uncontrolled proliferation and tumorigenesis. Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/C^CDH1 resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer in vivo. Reciprocal inhibition of PIN1 and APC/C^CDH1 is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy.

Publication types

Preprint