Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma

Luo, Mingyu; Zhou, Ye; Gu, Wei-ming; Wang, Cheng; Shen, Ning-Xiang; Dong, Jiang-Kai; Lei, Hui‐Min; Tang, Ya‐Bin; Liang, Qian; Zou, Jing-Hua; Xu, Lu; Ma, Ping; Zhuang, Guanglei; Bi, Ling; Xu, Ling; Zhu, Liang; Chen, Hongzhuan; Shen, Ying

doi:10.1158/0008-5472.can-21-4074

Cited by 26 publications

(10 citation statements)

References 50 publications

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“…PSAT1, a metabolic enzyme, plays a metabolic and nonmetabolic function in carcinogenesis, involved in serine biosynthesis and, moreover, elevating in lung adenocarcinoma for EGFR inhibitor resistance and tumor metastasis. 22 Most strikingly, MBNL3 is upregulated in fetal livers, depleted in adult livers, and restored high expression in HCC patients. These demonstrated that MBNL3 is critical for liver evolution and especially for HCC tissues.…”

Section: Resultsmentioning

confidence: 99%

TATA-box-binding protein promotes hepatocellular carcinoma metastasis through epithelial-mesenchymal transition

Cao

Yang

Luo

et al. 2023

Hepatology Communications

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Background: HCC characterizes malignant metastasis with high incidence and recurrence. Thus, it is pivotal to discover the mechanisms of HCC metastasis. TATA-box-binding protein (TBP), a general transcriptional factor (TF), couples with activators and chromatin remodelers to sustain the transcriptional activity of target genes. Here, we investigate the key role of TBP in HCC metastasis. Methods: TBP expression was measured by PCR, western blot, and immunohistochemistry. RNA-sequencing was performed to identify downstream proteins. Functional assays of TBP and downstream targets were identified in HCC cell lines and xenograft models. Luciferase reporter and chromatin immunoprecipitation assays were used to demonstrate the mechanism mediated by TBP. Results: HCC patients showed high expression of TBP, which correlated with poor prognosis. Upregulation of TBP increased HCC metastasis in vivo and in vitro, and muscleblind-like-3 (MBNL3) was the effective factor of TBP, positively related to TBP expression. Mechanically, TBP transactivated and enhanced MBNL3 expression to stimulate exon inclusion of lncRNA-paxillin (PXN)-alternative splicing (AS1) and, thus, activated epithelial-mesenchymal transition for HCC progression through upregulation of PXN. Conclusions: Our data revealed that TBP upregulation is an HCC enhancer mechanism that increases PXN expression to drive epithelial-mesenchymal transition.

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Section: Resultsmentioning

confidence: 99%

TATA-box-binding protein promotes hepatocellular carcinoma metastasis through epithelial-mesenchymal transition

Cao

Yang

Luo

et al. 2023

Hepatology Communications

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“…At the same time, some drug resistance mechanisms may also make the tumor more capable of metastasis ( 159 ). For example, in lung adenocarcinoma, overexpression of PSAT1 may lead to tumor metastasis and erlotinib resistance ( 104 , 104 ). In addition, because the current treatment strategy for tumor metastasis does not make adjustments for the different occurrence of metastasis, but adopts an identical strategy, which may be an important factor leading to drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically, the activation of metabolic activity of PSAT1 could inhibit ROS-dependent JNK/c-Jun pathway to inhibit apoptosis. PSAT1 could also interact with IQGAP1 and then activate STAT3 to promote migration independent of its metabolic activity ( 104 ). Another essential enzyme is PSPH, which was also observed to be upregulated in lung metastases.…”

Section: Serine and Glycine Metabolismmentioning

confidence: 99%

Amino acid metabolic reprogramming in tumor metastatic colonization

Wang

Chen

et al. 2023

Front. Oncol.

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Metastasis is considered as the major cause of cancer death. Cancer cells can be released from primary tumors into the circulation and then colonize in distant organs. How cancer cells acquire the ability to colonize in distant organs has always been the focus of tumor biology. To enable survival and growth in the new environment, metastases commonly reprogram their metabolic states and therefore display different metabolic properties and preferences compared with the primary lesions. For different microenvironments in various colonization sites, cancer cells must transfer to specific metabolic states to colonize in different distant organs, which provides the possibility of evaluating metastasis tendency by tumor metabolic states. Amino acids provide crucial precursors for many biosynthesis and play an essential role in cancer metastasis. Evidence has proved the hyperactivation of several amino acid biosynthetic pathways in metastatic cancer cells, including glutamine, serine, glycine, branched chain amino acids (BCAAs), proline, and asparagine metabolism. The reprogramming of amino acid metabolism can orchestrate energy supply, redox homeostasis, and other metabolism-associated pathways during cancer metastasis. Here, we review the role and function of amino acid metabolic reprogramming in cancer cells colonizing in common metastatic organs, including lung, liver, brain, peritoneum, and bone. In addition, we summarize the current biomarker identification and drug development of cancer metastasis under the amino acid metabolism reprogramming, and discuss the possibility and prospect of targeting organ-specific metastasis for cancer treatment.

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“…It catalyzed the phosphohydroxypyruvate oxidized by PHGDH to produce phosphoserine, which is then dephosphorylated by 1-3-phosphoserine phosphatase (PSPH) to form serine. PSAT1 expression is elevated in colon cancer and lung adenocarcinoma, and has been shown to enhance cell proliferation, metastasis, and chemoresistance ( 31 , 32 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis reveals effects of leukemogenic SHP2 mutations in biosynthesis of amino acids signaling

Zhao

Chang²,

Hu³

et al. 2023

Front. Oncol.

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Gain-of-function mutations of SHP2, especially D61Y and E76K, lead to the development of neoplasms in hematopoietic cells. Previously, we found that SHP2-D61Y and -E76K confer HCD-57 cells cytokine-independent survival and proliferation via activation of MAPK pathway. Metabolic reprogramming is likely to be involved in leukemogenesis led by mutant SHP2. However, detailed pathways or key genes of altered metabolisms are unknown in leukemia cells expressing mutant SHP2. In this study, we performed transcriptome analysis to identify dysregulated metabolic pathways and key genes using HCD-57 transformed by mutant SHP2. A total of 2443 and 2273 significant differentially expressed genes (DEGs) were identified in HCD-57 expressing SHP2-D61Y and -E76K compared with parental cells as the control, respectively. Gene ontology (GO) and Reactome enrichment analysis showed that a large proportion of DEGs were involved in the metabolism process. Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis showed that DEGs were the mostly enriched in glutathione metabolism and biosynthesis of amino acids in metabolic pathways. Gene Set Enrichment Analysis (GSEA) revealed that the expression of mutant SHP2 led to a significant activation of biosynthesis of amino acids pathway in HCD-57 expressing mutant SHP2 compared with the control. Particularly, we found that ASNS, PHGDH, PSAT1, and SHMT2 involved in the biosynthesis of asparagine, serine, and glycine were remarkably up-regulated. Together, these transcriptome profiling data provided new insights into the metabolic mechanisms underlying mutant SHP2-driven leukemogenesis.

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Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma

Cited by 26 publications

References 50 publications

TATA-box-binding protein promotes hepatocellular carcinoma metastasis through epithelial-mesenchymal transition

TATA-box-binding protein promotes hepatocellular carcinoma metastasis through epithelial-mesenchymal transition

Amino acid metabolic reprogramming in tumor metastatic colonization

Transcriptome analysis reveals effects of leukemogenic SHP2 mutations in biosynthesis of amino acids signaling

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