Scientists from West China Hospital of Sichuan University have discovered a new target for tumor metabolic therapy!

Introduction: Tumor cells metabolize through glycolysis even in the presence of sufficient oxygen, consuming a large amount of glucose and eventually producing lactic acid.
This phenomenon is called tumor aerobic glycolysis, also known as the Warburg effect
.
There is an important regulator in this process, namely M2-type pyruvate kinase (PKM2), which catalyzes its upstream substrate phosphoenolpyruvate PEP to pyruvate
.
PKM2 is highly expressed in proliferating cells, especially tumor cells
.

On August 17, Prof.
Lin Ping and Prof.
Li Kai from West China Hospital of Sichuan University jointly published a study "DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2" in "Signal Transduction and Targeted Therapy", and found that DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2.
PKM2-mediated metabolic reprogramming drives colorectal cancer progression
.

Doi: 10.
1038/s41392-022-01096-7.

Research Background

01

Colorectal cancer (CRC) is the third most common malignancy, and recent studies have shown that metabolic reprogramming is critical for tumorigenesis and metastasis
.
As a key rate-limiting enzyme in the glycolytic pathway, PKM2 is significantly upregulated in a variety of tumors
.

It was recently found that PKM2 can also translocate into the nucleus, where it functions as a protein kinase and co-transcription factor, leading to the transactivation of metabolic and proliferation genes, however, the molecular mechanisms underlying the dynamic accumulation and nuclear localization of PKM2 during tumorigenesis remain unclear.
Not entirely clear
.
Human DExD-box helicase 39B (DDX39B), a member of the DEAD-box protein family, is involved in many steps of RNA metabolism and plays a crucial role in tumor development, however, the specific role of DDX39B in CRC and the detailed mechanism is unclear
.

research process

02

The researchers identified the target gene DDX39B related to the occurrence and metastasis of CRC through the GEO database (Figure 1), and verified through the TCGA database and large sample clinical data, and found that DDX39B was significantly highly expressed in CRC and negatively correlated with the prognosis of CRC patients.
And promote the growth and metastasis of CRC in vivo and in vitro
.
To further determine the mechanism of DDX39B upregulation in CRC, the researchers found that Sp1 could activate DDX39B transcription in CRC cells by analyzing and verifying the promoter of DDX39B
.

Figure 1.
Screening of target genes related to CRC occurrence and metastasis by GEO database

In addition, in order to clarify the mechanism of DDX39B, the researchers identified the interacting protein PKM2 of DDX39B by immunoprecipitation combined with mass spectrometry, and found that the interaction between DDX39B and PKM2 can prevent its degradation, and DDX39B can promote the ERK-independent PKM2 nucleus.
translocated (Fig.
2), and DDX39B promoted tumor progression by enhancing aerobic glycolysis by enhancing nuclear PKM2 function in CRC cells
.

Figure 2.
DDX39B promotes ERK-independent nuclear translocation of PKM2

In order to further clarify the interaction mechanism between DDX39B and PKM2, the researchers analyzed the spatial structure of DDX39B and PKM2 through structural bioinformatics and conducted docking tests, and found that Arg319 on DDX39B is necessary for PKM2 binding and the ability of DDX39B to promote the occurrence and development of CRC.
of (Figure 3)
.
In addition, we also found that nuclear PKM2-mediated Warburg effect is also essential for DDX39B-triggered CRC tumorigenicity and metastasis
.

Figure 3.
Arg319 is essential for DDX39B to promote CRC occurrence and development

Significance

05

This study identifies DDX39B as a key promoter of the Warburg effect leading to malignant progression of CRC, reveals the clinical value of DDX39B, and provides a rationale for DDX39B-mediated metabolic plasticity by screening to target DDX39B or block DDX39B-PKM2 Combined inhibitors may be a new strategy for CRC therapy
.

References:

Zhao G, Yuan H, Li Q, et.
al.
DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2.
Signal Transduct Target Ther.
2022 Aug 17;7(1):275.
doi: 10.
1038/s41392- 022-01096-7.