Study of the Molecular Mechanism Underlying Psat1-Induced Cancer Metastasis

Cancer metastasis leading to the dysfunction of invaded organs is a main cause of the reduced survival rates in cancer patients. However, the molecular mechanism for cancer metastasis remains unclear. Recently, metabolic reprogramming was becoming a most popular topic in cancer research and has been considered to be associated with mechanism for cancer progression (e.g. metastasis, recurrence and drug resistance), even though there are still largely unknown about its action in cancer progression and usefulness for translational practice. Notably, it has been demonstrated that metabolic reprogramming likely benefits cancer evolution via activating the de novo synthesis of macromolecules, e.g. proteins. Therefore, the understanding of metabolic alterations in amino acid biosynthesis is capable of bridging the gap from metabolic reprogramming to cancer progression but also identifying new drug targets for cancer therapy. Because the enzymes involved in serine biosynthesis have been correlated with cancer development, we thus performed immunohistochemstry (IHC) staining against cancer tissue microarray using their specific antibodies. The data from IHC staining, as well as globally gene meta-analysis, revealed that the up-regulation of phosphoserine aminotransferase 丨（PSAT1), an enzyme catalyzes the reversible conversion of 3-phosphohydroxypyruvate to phosphoserine in serine biosynthesis, is extensively found in advanced cancers and significantly correlates with a poorer prognosis in cancer patients. Moreover, our results showed that PSAT1 -knockdown (KD) significantly suppresses the in vitro and in vivo metastatic abilities of highly metastatic lung cancer cells; conversely, PSAT 1 -overexpression (OE) obviously enhances the in vitro and in vivo metastatic abilities of poorly metastatic lung cancer cells. The data from Ingenuity Pathways Analysis (IPA) for microarray data derived from highly metastatic cancer cells without or with PSAT1-KD demonstrated that PSAT 1 -KD results in the dramatically reduced expression of several genes involved in cancer metastasis and likely inhibits the activation of transcription factors that are able to regulate the metastasis-associated gene expression. However, further complementary experiment is still needed to validate these findings and the mechanism by which the PSAT1 -induced metabolic alteration of serine biosynthesis promotes lung cancer metastasis remained to be determined. In this proposed 3-years study, we will investigate the following specific aims.⑴ To determine the downstream effector transcription factor(s) and gene(s) that mediates the PSAT1-promoted metastatic abilities of lung cancer cells in vitro and in vivo. (2) To elucidate the transcriptional regulation for the gene(s) that committedly executes the PSATI-triggered cancer metastasis. (3) To investigate the functional consequences of serine biosynthetic reprogramming on the PSATI-promted cancer cell metastasis. (4) To identify the protein-protein interaction(s) of which regulates the PSATI-promted cancer cell metastasis. Data from the proposed study may uncover the mechanism by which PSAT1 induces metabolic reprogramming to promote cancer metastasis. On the other hand, the identified PSATI-associated PPIs upon cancer metastasis might provide an opportunity and serve as the target to develop small-molecule or peptide PPI inhibitors to combat metastatic malignancies and even selectively kill cancers with PSAT1-OE.