With an H-index of 78 and more than 38,000 citations, he has been selected as a Elsevier China Highly Cited Researcher for 7 consecutive years and has been selected into the "Top 2% of the World's Top Scientists" released by Stanford University for many times.
In addition, SAG/RBX2 has been cloned for the first time in the world, and it has been identified as the catalytic core molecule of CRL (Cullin-RING ligase) E3 ligase, and several small molecule inhibitors and patents against this ligase and pseudomimetic E1/E2 enzyme have been obtained.
He is Sun Yi, who is currently serving as the Qiushi Chair Professor at Zhejiang University, and is employed by the Institute of Oncology and the Institute of Translational Medicine of the Second Affiliated Hospital of Zhejiang University School of Medicine. From 2014 to 2018, Sun Yi served as the founding dean of the Institute of Translational Medicine at Zhejiang University.
Figure | Sun Yi (Source: Sun Yi)
Prior to returning to China, he held positions at the National Cancer Institute, Parke-Davis and Pfizer Global Research in Cancer Molecules, and the University of Michigan.
Recently, he and his team revealed the key role of the UBE2F-CRL5ASB11-DIRAS2 pathway in pancreatic cancer lesions, providing new clues for the pathogenesis of pancreatic cancer, and is expected to become a new indicator for selecting new targets for anti-pancreatic cancer and evaluating patient prognosis.
（来源：Developmental Cell）
In this study, they identified UBE2F, an important synergistic gene for KRAS in pancreatic cancer, as well as the DIRAS2 protein that inhibits the RAS-MAPK-c-MYC pathway.
It also demonstrated that MLN4924, a small molecule inhibitor of anthropomorphic E1 in clinical trials, can inhibit the occurrence and progression of pancreatic cancer by inhibiting the UBE2F-SAG-CUL5 axis, leading to the accumulation of DIRAS2.
According to reports, pancreatic cancer is one of the common malignant tumors of the digestive tract. To date, there have been no breakthroughs in the treatment of pancreatic cancer.
其中，胰腺导管腺癌（Pancreatic ductal adenocarcinoma，PDAC）是最常见的病理类型。
Many chemotherapy or immunotherapy strategies that have worked well in other cancer types are largely ineffective against pancreatic ductal glands.
Due to the insidious pathogenesis of pancreatic ductal glands, the difficulty of early diagnosis, the rapid progression, and the lack of effective treatment methods, the prognosis of patients is extremely poor, and they are known as the "king of cancer".
Studies have shown that the occurrence and development of pancreatic cancer are closely related to abnormal changes in key genes. More than 90% of patients with pancreatic cancer have mutations in the oncogene KRAS.
Deletion mutations in tumor suppressor genes such as CDKN2A, TP53, and SMAD4 synergistically interact with the activation of KRAS, promoting the growth, metastasis, and immune escape of pancreatic cancer.
Therefore, it is of great theoretical significance and clinical value to study the molecular biological mechanism of the occurrence and development of pancreatic cancer.
In recent years, a number of studies have found that the mimemorphic modification pathway of proteins is overactivated in a variety of tumors, which is closely related to the occurrence, development, metastasis, and poor prognosis of patients.
The synergistic effect of the couplingase UBE2F with the ligase SAG allows CUL5 to be mimetricized, thereby activating the ubiquitin ligase CRL5, resulting in ubiquitinated degradation of the tumor suppressor protein.
The previous study of Yi Sun's team found that in pancreatic cancer tissues, NEDD8 and SAG, key components of the UBE2F-SAG-CUL5 axis, were abnormally high and positively correlated with poor prognosis of patients.
Therefore, they speculated that the UBE2F-SAG-CUL5 axis may play an important role in the occurrence and progression of pancreatic cancer.
Based on this, the team attempted to explore the role and mechanism of UBE2F in pancreatic cancer through KrasG12D-induced conditional knockout of Ube2f in a mouse pancreatic cancer model.
Although this is a complex subject, it can be clearly divided into four steps:
In the first step, a KrasG12D-induced, conditional knockout of Ube2f pancreatic cancer model was constructed, through which they found that the absence of Ube2f inhibited cholecystokinin Cerulein-induced pancreatitis and could effectively inhibit the occurrence and progression of pancreatic tumors.
In the second step, through the proteomic data accumulated by the research group, they found DIRAS2, a key protein in UBE2F that promotes the occurrence and development of pancreatic cancer.
In the third step, through a series of molecular biology experiments, DIRAS2 was confirmed to be a key ubiquitinated degradation substrate protein of the UBE2F-SAG-CUL5 axis.
In the fourth step, RNA silencing screening is used to find the specific substrate recognition protein ASB11. CUL5 binds to the substrate protein DIRAS2 by recognizing the protein ASB11 through the substrate, resulting in ubiquitinated degradation of DIRAS2.
Finally, in vivo experiments, it was proved that the knockout of DIRAS2 can promote the occurrence and development of pancreatic cancer.
According to the research group, the deletion of UBE2F significantly inhibits the formation of pancreatic tumors caused by KRAS mutations, indicating that it plays a crucial role in the occurrence and progression of pancreatic cancer.
In order to further verify the tumor suppressor effect of DIRAS2 in pancreatic cancer, the research team found in vitro cell experiments that DIRAS2 knockdown can promote the proliferation of pancreatic cancer cells, and after DIRAS2 knockout in mice, it will promote the occurrence and development of pancreatic cancer.
When DIRAS2 and UBE2F are knocked out simultaneously in mice, most of the tumor suppressants caused by UBE2F knockout are eliminated. This also proves once again that UBE2F can promote the occurrence and progression of pancreatic cancer by reducing the protein level of DIRAS2.
Through mechanistic research, the team found that UBE2F promoted the ubiquitination and degradation of the tumor suppressor protein DIRAS2 by activating the CRL5 ligase, relieving the inhibitory effect of DIRAS2 on the MAPK/c-MYC signaling pathway, thereby promoting the proliferation of pancreatic cancer cells.
In addition, the team identified the ASB11 protein in the CRL5 component and directly bound it to DIRAS2, thereby facilitating its degradation.
At the same time, they found that UBE2F and DIRAS2 were highly and poorly expressed in human pancreatic cancer tissues, respectively, and showed positive and negative correlations with poor prognosis of patients.
最终，相关论文以（The UBE2F-CRL5ASB11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells）为题发在 Developmental Cell（IF 11.8）[1]。
Chang Yu and Chen Qian are the co-first authors, and Sun Yi is the corresponding author.
图 | 相关论文（来源：Developmental Cell）
However, in this study, although they found DIRAS2, a key tumor suppressor protein, to exist as a substrate for the UBE2F-SAG-CUL5 axis, knockdown of DIRAS2 only alleviates most of the tumor suppressor effects caused by UBE2F knockout.
Therefore, there should be other key genes besides DIRAS2 that mediate the role of UBE2F in promoting pancreatic carcinogenesis. Subsequently, the team will search for new key substrate proteins through mass spectrometry analysis of mouse pancreatic cancer tissues.
In addition, the special immune microenvironment of pancreatic cancer determines that pancreatic cancer is not effective for immunotherapy. Previous studies have shown that inhibition of KRAS can promote the recruitment of activated CD4+ and CD8+ T cells in tumor tissues, and promote the activation of antigen-presenting cells.
Therefore, the UBE2F-CRL5ASB11-DIRAS2 axis also plays an important role in the pancreatic cancer immune microenvironment by regulating KrasG12D. Therefore, inhibiting this axis to promote pancreatic cancer from a "cold" tumor to a "hot" tumor, so as to exert a synergistic effect with immunotherapy, is also a research direction they will focus on in the future.
In addition, they are developing specific small molecule inhibitors for UBE2F and CUL5 mimetic modifications, showing good tumor suppression in lung cancer cells and mouse tumor models, which were published in the journal Signal Transduction and Targeted Therapy in 2022.
It is believed that in the near future, the research group can effectively control the development of pancreatic cancer by specifically inhibiting the UBE2F-SAG-CUL5 axis and promoting the accumulation of tumor suppressor protein DIRAS2.
It is also reported that in the research and development of UBE2F and SAG-CUL5 small molecule inhibitors, the research group is cooperating with Lianxing Biotech to use AI for computer simulation, so as to achieve structural optimization and improvement of biological activity.
They expect to develop a new generation of small molecule drugs with high efficiency, low toxicity, novel structure, simple molecule, strong druggability, and independent intellectual property rights.
Resources:
1.Chang, Y., Chen, Q., Li, H., Xu, J., Tan, M., Xiong, X., & Sun, Y. (2024). The UBE2F-CRL5ASB11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells. Developmental Cell.
Operation/typesetting: Luo Yi, He Chenlong