The Zhejiang University team discovers a new pro-cancer pathway and is working w

2024-07-29

H-index of 78, with over 38,000 citations for his papers, he has been named a Highly Cited Chinese Researcher by Elsevier for seven consecutive years, and has been listed multiple times in the "World's Top 2% Scientists" list published by Stanford University.

He was the first in the world to clone SAG/RBX2 and identify it as the catalytic core molecule of the CRL (Cullin-RING ligase) E3 ligase, and has since obtained several types of small molecule inhibitors and patents against this ligase and the neddylation E1/E2 enzymes.

He is Sun Yi, currently serving as a "Qiushi" Chair Professor at Zhejiang University, and is dual-appointed at the Cancer Research Institute and the Institute of Translational Medicine at 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.

Before returning to China, he held positions at the National Cancer Institute in the United States, the global research department of cancer molecular science at Parke-Davis and Pfizer (Wyeth), and the University of Michigan.

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Not long ago, he and his team revealed the key role of the UBE2F-CRL5ASB11-DIRAS2 pathway in pancreatic cancer, providing new clues for the study of the pathogenesis of pancreatic cancer, and it is expected to become a new target for the selection of anti-pancreatic cancer and a new indicator for assessing patient prognosis.In this study, they identified the important synergistic gene UBE2F of KRAS in pancreatic cancer, as well as the DIRAS2 protein that inhibits the RAS-MAPK-c-MYC pathway.

 

It also demonstrated that the small molecule inhibitor MLN4924 of the neddylation E1 in the clinical trial phase can inhibit the occurrence and development of pancreatic cancer by inhibiting the UBE2F-SAG-CUL5 axis, leading to the accumulation of DIRAS2.

 

It is reported that pancreatic cancer is one of the common malignant tumors of the digestive tract. So far, breakthrough progress has not been made in the treatment of pancreatic cancer.

 

Among them, pancreatic ductal adenocarcinoma (Pancreatic ductal adenocarcinoma, PDAC) is the most common pathological type.

 

Many chemotherapy strategies or immunotherapy strategies that have achieved good results in other types of cancer are basically ineffective for pancreatic ductal adenocarcinoma.Due to the insidious onset of pancreatic ductal adenocarcinoma, difficulty in early diagnosis, rapid progression, and lack of effective treatment options, the prognosis for patients is extremely poor, earning it the moniker "king of cancers."

Research indicates that the occurrence and progression of pancreatic cancer are closely related to abnormal changes in key genes. Over 90% of patients with pancreatic cancer have mutations in the oncogene KRAS.

The loss of mutations in tumor suppressor genes such as CDKN2A, TP53, and SMAD4, in synergy with the activation of KRAS, promotes the growth, metastasis, and immune evasion of pancreatic cancer.

Therefore, in-depth study of the molecular biological mechanisms of the occurrence and development of pancreatic cancer has significant theoretical and clinical value.

In recent years, multiple studies have found that the prenylation modification pathway of proteins is overactivated in various tumors, which is closely related to the occurrence, development, metastasis of cancer, and the poor prognosis of patients.The ubiquitination enzyme UBE2F works in concert with the E3 ligase SAG to enable ubiquitination modification of CUL5, thereby activating the ubiquitin ligase CRL5, which leads to the ubiquitination and degradation of tumor suppressor proteins.

 

Yi Sun's team's previous research found that in pancreatic cancer tissues, key components of the ubiquitination pathway UBE2F-SAG-CUL5 axis, NEDD8 and SAG, are abnormally overexpressed and positively correlated with poor patient prognosis.

 

Therefore, they speculate that the UBE2F-SAG-CUL5 axis may play an important role in the occurrence and development of pancreatic cancer.

 

Based on this, the team conditionally knocked out Ube2f in a mouse model of pancreatic cancer induced by KrasG12D, attempting to explore the role and mechanism of UBE2F in pancreatic cancer through this model.

 

Although this is a complex subject, in their eyes, it can be clearly divided into four steps:Step one, they constructed a pancreatic cancer model with KrasG12D induction and conditional knockout of Ube2f. Through this, they discovered that the absence of Ube2f suppressed pancreatitis induced by cholecystokinin Cerulein and effectively inhibited the occurrence and development of pancreatic tumors.

Step two, by leveraging the proteomics data accumulated by the research group, they identified the key protein DIRAS2 that promotes the occurrence and development of pancreatic cancer.

Step three, through a series of molecular biology experiments, they confirmed that DIRAS2 is a key ubiquitinated degradation substrate protein of the UBE2F-SAG-CUL5 axis.

Step four, by using RNA silencing screening, they found the specific substrate recognition protein ASB11. CUL5 can bind with the substrate protein DIRAS2 through the substrate recognition protein ASB11, leading to the ubiquitination and degradation of DIRAS2.

Finally, in vivo experiments proved that the knockout of DIRAS2 can promote the occurrence and development of pancreatic cancer.The research team stated that the absence of UBE2F significantly inhibited the formation of pancreatic tumors caused by KRAS mutations, indicating its crucial role in the occurrence and development of pancreatic cancer.

To further verify the tumor-suppressing effect of DIRAS2 in pancreatic cancer, the research team found in vitro cellular experiments that the knockdown of DIRAS2 could promote the proliferation of pancreatic cancer cells, and the knockout of DIRAS2 in mice would promote the occurrence and development of pancreatic cancer.

When DIRAS2 and UBE2F are simultaneously knocked out in mice, it would eliminate most of the tumor-suppressing effects caused by the knockout of UBE2F. This also once again confirms that UBE2F can promote the occurrence and development of pancreatic cancer by reducing the protein level of DIRAS2.

Through mechanism research, the team found that UBE2F promotes the ubiquitination and degradation of the tumor-suppressing protein DIRAS2 by activating the CRL5 ligase, relieving the inhibitory effect of DIRAS2 on the MAPK/c-MYC signaling pathway, and thereby promoting the proliferation of pancreatic cancer cells.

In addition, the team also found the ASB11 protein in the CRL5 component, which directly binds to DIRAS2 and promotes its degradation.At the same time, they found that UBE2F and DIRAS2 exhibited high and low expression respectively in human pancreatic cancer tissues, and were positively correlated with poor prognosis and negatively correlated with poor prognosis in patients.

 

Ultimately, the related paper was published in Developmental Cell (IF 11.8) with the title "The UBE2F-CRL5ASB11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells" [1].

 

Chang Yu and Chen Qian are co-first authors, and Sun Yi serves as the corresponding author.

 

However, in this study, although they found the key tumor suppressor protein DIRAS2 as a substrate of the UBE2F-SAG-CUL5 axis, the knockdown of DIRAS2 only partially relieved the tumor-suppressing effect brought about by the knockdown of UBE2F.

 

Therefore, in addition to DIRAS2, there should be other key genes that mediate the role of UBE2F in promoting the occurrence of pancreatic cancer. Subsequently, the team will search for new key substrate proteins through mass spectrometry analysis of mouse pancreatic cancer tissues.In addition, the unique immunological microenvironment of pancreatic cancer determines its poor response to immunotherapy. Several previous studies have shown that the inhibition of KRAS can promote the recruitment and activation of tumor tissue CD4+ and CD8+ T cells, and promote the activation of antigen-presenting cells.

Therefore, the UBE2F-CRL5ASB11-DIRAS2 axis plays an important role in the immunological microenvironment of pancreatic cancer by regulating KrasG12D. Hence, inhibiting this axis to promote the transformation of pancreatic cancer from a "cold" tumor to a "hot" tumor, thereby exerting a synergistic effect with immunotherapy, is also a research direction they will focus on in the future.

Furthermore, they are developing specific small molecule inhibitors targeting the ubiquitination modification of UBE2F and CUL5, which have shown good tumor suppression effects in lung cancer cells and mouse tumor models. The related paper was 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 the tumor suppressor protein DIRAS2.

It is also reported that in the development of small molecule inhibitors for UBE2F and SAG-CUL5, the research group is cooperating with Lianxing Biotech Company, using AI for computer simulation to achieve structural optimization and enhancement of biological activity.They are looking forward to developing a new generation of highly efficient, low toxicity, novel structure, simple molecules, strong druggability, and with independent intellectual property rights of small molecule drugs.

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