Bowel cancer (CRC) is one of the most common malignancies of the digestive tract. In the past few decades, due to changes in dietary structure and living habits, the incidence of CRC among urban and rural residents in China has continued to increase. At present, CRC has become the top five malignant tumors in China. About 25% of patients with CRC are diagnosed with distal metastases at the time of initial diagnosis, and about 30% of patients with crcs who do not have distal metastases at the time of initial diagnosis also develop distal metastases later in life. Metastasis is a multi-step cascade of processes tightly regulated by a series of cell signaling proteins that cause more than 90% of human cancer deaths. Studying the molecular mechanisms that regulate metastasis has important implications for the treatment of CRC.
Abnormal cellular metabolism is closely related to the occurrence and development of tumors. Loss of metabolic control has become an important feature of cancer. Serine is an important non-essential amino acid that has multiple uses for tumor cells: for protein synthesis; for participation in the synthesis of sphingomyelins and phospholipids as a precursor to glycine and cysteine; and for the generation of glycine and one carbon units for the synthesis of porphyrin, thymidine, purine, glutathione, and sam in a folic acid-mediated one-carbon pathway. Serine metabolism not only provides the necessary precursors for the synthesis of proteins, nucleic acids and lipids in tumor cells, but also provides reducing power for the maintenance of redox homeostasis in tumor cells. Therefore, serine metabolism is essential for the growth of tumors. However, whether and how serine metabolism is involved in tumor metastasis is unclear.
On November 1, 2021, The Yang Weiwei Research Group and collaborative team of the Center for Excellence in Molecular and Cell Science (Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences published an article in the journal journal journal of clinical investigation: cul4a-ddb1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased s-adenosylmethionine 。 The study found that bowel cancer (CRC) cells enhanced the activity of phosphoglycerate dehydrogenase (phgdh), a key enzyme in serine synthesis, by inducing monountination modifications, thereby promoting serine synthesis and one-carbon unit metabolism, increasing the content of intracellular s-adenosyl methionine (sam), and thus accelerating CRC liver metastasis.
The Yang Weiwei group found that the monountination modification of phgdh, a key enzyme in the serine synthesis pathway, promoted CRC transfer. The ubiquitin ligase complex cultura4a-ddb1-mediated monountination modification of the phgdh k146 site promoted the interaction between phgdh and the chaperone dnaja1, thereby promoting the formation of phgdh tetramers and upregulating the enzymatic activity of phgdh; the increase in phgdh activity increased the content of its downstream metabolite sam in the cell; and the high level of sam selectively activated the methyltransferase setd1a, It promoted the tripomethylation (h3k4me3) modification of histone h3k4 of the cell adhesion gene lamc2 and cyr61 promoters, thereby promoting the expression of lanc2 and cyr61 and the liver metastasis of CRC.
By analyzing a large sample of CRC patients, they found that the sam content in the tumor tissue at the metastatic end of the liver was higher than that of the tumor tissue at the in situ end of the CRC, and the serum content in the patients with metastatic recurrence was higher in the serum of the patients with metastatic recurrence.
This work discovered a new function in the regulation of serine metabolism to promote CRC metastasis; revealed a new mechanism for monountination modifications to regulate phgdhh activity and SAM production to promote CRC metastasis; suggested that blocking the serine synthesis pathway can inhibit CRC liver metastasis, and that the content of SAM in tumor tissue and serum can predict CRC metastasis and prognosis.
Professor Yang Weiwei, Professors David Li and Xinxiang Li of the Affiliated Cancer Hospital of Fudan University and Professor Wang Xiongjun of Guangzhou University are the co-corresponding authors of the paper. Dr. Yajuan Zhang, Dr. Yu Hua of Guangzhou University, and Dr. Jie Zhang of ShanghaiTech University were the co-first authors of the paper.
Original link:
https://www.jci.org/articles/view/146187