PSPH Mediates the Metastasis and Proliferation of Non-small Cell Lung Cancer through MAPK Signaling Pathways

Liao, Li; Ge, Min; Zhan, Qimin; Huang, Run; Ji, Xiaoyu; Liang, Xiaohua; Zhou, Xinli

doi:10.7150/ijbs.29203

Cited by 26 publications

(28 citation statements)

References 25 publications

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“…Consistent with our findings, PSPH expression has also been shown to be increased in breast cancer [ 41 ] and colorectal cancer and correlate with enhanced invasion and metastasis [ 42 ]. Furthermore, PSPH has also been shown to be important for proliferation and metastasis of non-small–cell lung cancer and cutaneous squamous cell carcinoma [ 21 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1

et al. 2021

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Metabolic deregulation, a hallmark of cancer, fuels cancer cell growth and metastasis. Here, we show that phosphoserine phosphatase (PSPH), part of the serine metabolism pathway, is upregulated in patient-derived melanoma samples. PSPH knockdown using short hairpin RNAs (shRNAs) blocks melanoma tumor growth and metastasis in both cell culture and mice. To elucidate the mechanism underlying PSPH action, we evaluated PSPH shRNA-expressing melanoma cells using global metabolomics and targeted mRNA expression profiling. Metabolomics analysis showed increase in 2-hydroxyglutarate (2-HG) levels in PSPH knockdown cells. 2-HG inhibits the TET family of DNA demethylases and the Jumonji family of histone demethylases (KDM and JMJD), which is known to impact gene expression. Consistent with these data, PSPH knockdown in melanoma cells showed reduced DNA 5-hydroxymethylcytosine (5hmC) and increased histone H3K4me3 modifications. 2-HG treatment also inhibited melanoma growth. The nCounter PanCancer Pathways Panel–based mRNA expression profiling revealed attenuation of a number of cancer-promoting pathways upon PSPH knockdown. In particular, PSPH was necessary for nuclear receptor NR4A1 expression. Ectopic NR4A1 expression partly rescued growth of melanoma cells expressing PSPH shRNA. Collectively, these results link PSPH to facilitation of melanoma growth and metastasis through suppression of 2-HG and thus activation of pro-oncogenic gene expression.

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Section: Discussionmentioning

confidence: 99%

PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1

et al. 2021

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“…Hence, downstream genes (excluding WT1) that could be regulated by WT1-AS were investigated by RNA-sEq. Combined with the KEGG enrichment data and cluster analyzes, 10 genes (PSPH [34,35], PHGDH [36,37], GSTO2 [38], CACNA2D1 [39,40], FYN [41], MAOB [42,43], ANPEP [44,45], ITGA2 [46,47], CTSS [48] and PRKCA [49] were selected for further explorations in view of their close association with cancer progression and prognosis. Our RT-qPCR assay validated that PSPH, GSTO2, FYN, and PHGDH could be regulated by WT1-AS, but not WT1 in GSCs.…”

Section: Discussionmentioning

confidence: 99%

Investigations into the effects and related upstream/downstream regulatory mechanisms of long non-coding RNA WT1-AS in the maintenance and development of gastric cancer stem cells in vitro and in vivo

Zhang¹,

Jin²,

Liu³

et al. 2021

Preprint

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Background Cancer stem cells (CSCs) are proposed to be responsible for almost all malignant phenotypes (e.g. heterogeneity, uncontrolled growth, metastasis, recurrence, chemoresistance) of tumors. Long non-coding RNA WT1 antisense RNA (WT1-AS) has been found to be involved in the regulation of lung cancer cell stemness. However, the roles and molecular mechanisms of WT1-AS in the maintenance and development of gastric cancer stem cells (GSCs) have not been investigated. Methods mRNA and protein expression was measured by RT-qPCR and western blot. CCK8 and Soft agar colony formation assays were performed to assess cell viability and colony clone formation ability. Cell cycle and apoptosis were determined by flow cytometry analysis. Cell transwell and wound healing analyses were carried out to assess cell migration ability. In vitro angiogenesis and 3D spheroid cultures assays were also performed. Moreover, in vitro experiments were carried out to explore the function of WT1-AS on tumor growth, metastasis and cell stemness. The upstream transcription factors or downstream genes of WT1-AS were screened through Bioinformatics, dual-luciferase assays and RNA-sequencing (RNA-seq) technology. Results Our present study demonstrated that WT1-AS knockdown or wilms tumor 1 (WT1) overexpression improved GSC proliferative and migratory capacities, promoted GSC EMT, enhanced GSC stemness, inhibited GSC apoptosis, potentiated the resistance of GSCs to 5-FU and induced HUVEC angiogenesis in vitro. WT1-AS loss or WT1 increase facilitated the formation of in-vitro 3D GSC aggregates. WT1-AS ameliorated the malignant phenotypes of GSCs by down-regulating WT in vitro. Additionally, WT1-AS inhibited tumor growth and metastasis, and reduced tumor stemness in GSCs-derived xenografts (s.c., i.p., and i.v.) in vivo. Furthermore, XBP1 was identified as an upstream regulator of WT1-AS in GSCs. RNA-seq and RT-qPCR data suggested that PSPH, GSTO2, FYN, and PHGDH might be the downstream targets of WT1-AS in GSCs. Conclusions Our data demonstrated that WT1-AS weakened the stem-cell like behaviors and characteristics of GSCs in vitro and in vivo by down-regulating WT1. Also, some upstream regulators and downstream targets of WT1-AS were identified in GSCs. Investigations on the molecular mechanisms underlying the complex phenotypes of GSCs might contribute to the better management of headaches in cancers.

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“…Our results are consistent with previous studies. Liao, Ge, et al (2019) reported that the downregulation of PSPH expression inhibited migration, invasion, and proliferation of nonsmall cell lung cancer cells. Bachelor et al (2011) reported that PSPH is highly induced in proliferative normal keratinocytes and in skin tumors, and knockdown of PSPH significantly reduced the proliferation of SCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…The most common pathway for PSPH to affect cancer is the serine synthesis pathway (Antonov et al, 2014, Sun et al, 2015). PSPH could mediate NSCLC cell proliferation and metastasis via the MAPK signaling pathway (Liao, Ge, et al, 2019). PSPH might be a molecular marker for the proliferation and metastasis of A549 cells by regulating the AKT/AMPK signaling pathway (Liao, Yu, et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

PSPH induces cell autophagy and promotes cell proliferation and invasion in the hepatocellular carcinoma cell line Huh7 via the AMPK/mTOR/ULK1 signaling pathway

Zhang

Wang²,

Zhang

et al. 2020

Cell Biology International

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Phosphoserine phosphatase (PSPH), a key enzyme of the l‐serine synthesis pathway, has been involved in cancer progression and survival. However, limited evidence revealed the PSPH influence on hepatocellular carcinoma (HCC). Herein, we observed that PSPH expression was upregulated in both HCC tissues and cell lines, which was determined by western blotting. TCGA database showed that the PSPH protein levels were significantly upregulated and affected patient survival rates in HCC. Then gain‐ and loss‐of‐function manipulations were performed by transfection with a pcDNA‐PSPH expression vector or a specific short interfering RNA against PSPH in Huh7 cells. Huh7 cell proliferation, stemness, invasion, and apoptosis were assessed by using CCK‐8 test, colony formation assay, Transwell assay, and Flow cytometry analysis, respectively, and levels of autophagy‐related proteins were detected by using western blotting. The results showed that PSPH could induce Huh7 cell autophagy, promote cell proliferation and invasion, and inhibit apoptosis. The knockdown of PSPH could inhibit Huh7 cell proliferation, invasion, and autophagy. Furthermore, PSPH activated Liver kinase B1 (LKB1) and TGF beta‐activated kinase 1 (TAK1), affected the adenosine 5′‐monophosphate‐activated protein kinase (AMPK)/mTOR/ULK1 signaling pathway, but could not activate calcium/calmodulin‐dependent protein kinase kinase (CaMKK) in Huh7 cells. Inhibition of either LKB1, TAK1, or AMPK could eliminate the effect of PSPH overexpression on Huh7 cell behaviors. However, inhibition of CaMKK could not influence the effect of PSPH overexpression on Huh7 cell behaviors. In conclusion, PSPH could induce autophagy, promote proliferation and invasion, and inhibit apoptosis in HCC cells via the AMPK/mTOR/ULK1 signaling pathway.

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PSPH Mediates the Metastasis and Proliferation of Non-small Cell Lung Cancer through MAPK Signaling Pathways

Cited by 26 publications

References 25 publications

PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1

PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1

Investigations into the effects and related upstream/downstream regulatory mechanisms of long non-coding RNA WT1-AS in the maintenance and development of gastric cancer stem cells in vitro and in vivo

PSPH induces cell autophagy and promotes cell proliferation and invasion in the hepatocellular carcinoma cell line Huh7 via the AMPK/mTOR/ULK1 signaling pathway

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