China's prostate cancer precision medicine research has been breakthrough

Wang Chen Ji, National Key Laboratory of Genetic Engineering, Fudan University, China, worked with Huang Haojie team of Mayo Medical Center and Sun Yinghao team of Second Military Medical University to achieve important research results in the field of precision medicine for prostate cancer. The results of the research were published online
.
cancer is currently the second largest cancer among men in the world. The genetic factors of the development of prostate cancer are complex and varied, there are significant tumor heterogeneity, and there are great differences in the molecular level of genome sequence, epigenetics and so on. At present, it is still very difficult to interpret the significance of genetic variation in tumor genome and find corresponding molecular targeting treatment.
the researchers focused on the molecular subsmope of prostate cancer with the SPOP mutation and for the first time found that the BET protein was the underlying agent of SPOP. BET proteins (BRD2, 3 and 4) are a class of exogenomic regulatory proteins that bind to acetylase histogenes, which control the transcription of growth-promoting, anti-apoptosis target genes such as C-Myc, PIM1, and BCL2. BET protein is the "star molecule" of anti-tumor drug design, which is currently targeted by the ode genetic protein. BET small molecule inhibitors such as JQ1 and iBET have shown excellent lethal effect on a variety of tumor cells and have been conducted in phase I clinical trials in prostate cancer. SPOP in normal cells promotes ubibinic degradation of BET proteins through protease pathways, keeping BET proteins at low levels.
SPOP mutation led to a significant decrease in its interaction with bet proteins and their ability to promote Ubibinization and degradation of BET proteins, which accumulate in large quantities in tumor tissue. BET protein accumulation promotes the transcription of cholesterol anabolic enzymes (e.g. FDFT1, DHCR24, etc.) and small GTP enzyme Rac1, which in turn activates the AKT-mTORC1 signaling path, which promotes the malignant proliferation of tumor cells. Interestingly, the accumulation of BET proteins caused by SPOP mutations in tumors greatly reduced the lethal effect of BET inhibitors on prostate cancer cells. However, when beta inhibitors are used in association with AKT inhibitors, the sensitivity of prostate cancer cells to BET inhibitors can be restored.
experts say the study partly sheds light on the molecular mechanisms by which SPOP mutations promote malignant proliferation of tumors, and reveals the natural resistance of SPOP mutation subtype prostate cancer to BET inhibitors. This information provides theoretical guidance for the precise treatment of this subsophony prostate cancer. (Source: Huang Xin, China Science Daily)