The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells

Cdr2 is a tumor antigen expressed in a high percentage of breast and ovarian tumors and is the target of a naturally occurring tumor immune response in patients with paraneoplastic cerebellar degeneration, but little is known of its regulation or function in cancer cells. Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. Loss of cdr2 leads to functional consequences for dividing cells, as they show aberrant mitotic spindle formation and impaired proliferation. Conversely, cdr2 overexpression is able to drive cell proliferation in tumors. Together, these data indicate that the onconeural antigen cdr2 acts during mitosis in cycling cells, at least in part through interactions with c-myc, to regulate a cascade of actions that may present new targeting opportunities in gynecologic cancer.

Cdr2是一类在高比例乳腺与卵巢肿瘤中表达的肿瘤抗原，同时也是副肿瘤性小脑变性（paraneoplastic cerebellar degeneration）患者体内天然抗肿瘤免疫应答的靶标，但目前学界对其在癌细胞中的调控机制与生物学功能仍知之甚少。本研究发现，Cdr2在肿瘤细胞中呈现细胞周期依赖性表达特征，其蛋白水平在有丝分裂期达到峰值。当细胞退出有丝分裂时，Cdr2会被后期促进复合物/周期体（anaphase promoting complex/cyclosome, APC/C）介导泛素化，并被蛋白酶体（proteasome）快速降解。此前我们的研究已证实Cdr2可与癌基因（oncogene）c-myc结合，本研究进一步拓展了该发现，证明Cdr2与c-myc可通过相互作用，在细胞历经有丝分裂的过程中协同调控依赖于c-myc的转录活动。缺失Cdr2会对增殖分裂的细胞产生功能性影响：这类细胞会出现异常的有丝分裂纺锤体形成，且增殖能力受损。反之，在肿瘤细胞中过表达Cdr2则可驱动细胞增殖。综合上述实验数据，本研究表明肿瘤神经抗原（onconeural antigen）Cdr2可在增殖细胞的有丝分裂阶段发挥调控作用，且至少部分通过与c-myc的相互作用，调控一系列级联反应，这或许能为妇科恶性肿瘤提供全新的靶向治疗思路。