Ke Shizhong, Dang Fabin, Wang Lin, Chen Jia-Yun, Naik Mandar T, Thavamani Abhishek, Liu Yansheng, Li Wenxue, Kim Nami, Naik Nandita M, Sui Huaxiu, Tang Wei, Qiu Chenxi, Koikawa Kazuhiro, Batalini Felipe, Wang Xiaodong, Clohessy John G, Heng Yujing Jan, Lahav Galit, Gray Nathanael S, Zho Xiao Zhen, Wei Wenyi, Wulf Gerburg M, Lu Kun Ping
Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
These authors contributed equally to this work.
Res Sq. 2023 Jan 19:rs.3.rs-2447544. doi: 10.21203/rs.3.rs-2447544/v1.
Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/C), 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 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 E3 ligase targets PIN1 for degradation in G1 phase, restraining G1/S transition; APC/C itself, after phosphorylation by CDKs, is inactivated by PIN1-catalyzed isomerization, promoting G1/S transition. In cancer, PIN1 overexpression and APC/C inactivation reinforce each other to promote uncontrolled proliferation and tumorigenesis. Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/C resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer Reciprocal inhibition of PIN1 and APC/C is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy.
细胞周期蛋白依赖性激酶（CDKs）介导的磷酸化作用会使后期促进复合物（APC/C）失活，APC/C是一种含有共激活因子CDH1的E3泛素连接酶，可促进G1/S期转换。PIN1是一种磷酸化导向的脯氨酸异构酶，也是主要的癌症信号调节因子。然而，关于磷酸化后APC/C的调控以及PIN1泛素连接酶的了解却很少。在此，我们发现了一种控制G1/S期适时转换的结构域导向的相互抑制作用：未磷酸化的APC/C E3连接酶在G1期靶向PIN1进行降解，从而抑制G1/S期转换；而APC/C本身在被CDKs磷酸化后，会被PIN1催化的异构化作用失活，进而促进G1/S期转换。在癌症中，PIN1的过表达和APC/C的失活相互增强，以促进不受控制的增殖和肿瘤发生。重要的是，联合抑制PIN1和CDK4/6可重新激活APC/C，导致PIN1降解并产生无法克服的G1期阻滞，这转化为对三阴性乳腺癌的协同抗肿瘤活性。PIN1和APC/C的相互抑制是控制G1/S期适时转换的一种新机制，可用于协同抗癌治疗。
