MERIT40 Enhances PHGDH Enzyme Activity And Promotes Development Of Breast Tumor

Breast cancer is one of the most common malignant tumors in women worldwide,It is also vital cause of death among women.It is necessary to study the molecular mechanism of breast cancer.The location of MERIT40 gene in human beings is the first known risk site for triple-negative breast cancer.Moreover,the TT genotype in rs8170 exon region was significantly associated with higher incidence of triple-negative breast cancer.MERIT40 protein is known as an important adaptor of BRCA1-A complex in double-stranded DNA damage repair.The function of MERIT40 is maintaining the stability of the whole BRCA1-A complex,promoting the composition of complex to mediate DNA damage repair.To explore the possible novel function of MERIT40 in breast cancer,our lab performed protein interaction screening using MERIT40 as a bait and found that PHGDH is a MERIT40 interacting protein.This interaction can be enhanced under the glucose starvation.PHGDH is the initial and rate-limiting enzyme of serine biosynthesis pathway(SSP).Many studies have confirmed that PHGDH is highly expressed in a variety of breast cancers.However,the regulation mechanism of PHGDH enzyme activity remains unknown.We found that Overexpression of MERIT40 enhanced the activity enzyme of PHGDH,while knockdown of MERIT40 reduced the enzyme activity of PHGDH.To a certain extent,purificated MERIT40 protein can rescue the decrease of PHGDH enzyme activity due to the lack of MERIT40 in vitro enzyme activity assay.Importantly,the existence of MERIT40 could maintain the survival of cells under the condition of glucose starvation.Furthermore,we found that knockdown of MERIT40 significantly reduced the growth rate of MDA-MB-468 orthotopic xenografts.These findings could provide a new drug target for breast cancer treatment.