A single mutation underlying phenotypic convergence for hypoxia adaptation on the Qinghai-Tibetan Plateau

Xu, Dongming; Yang, Cuiping; Shen, Qingwu; Pan, Shengkai; Liu, Zhen; Zhang, Tongzuo; Zhou, Xin; Lei, Menglong; Chen, Peng; Yang, Hui; Zhang, Tao; Guo, Yuan-Ting; Zhan, Xiangjiang; Chen, Yongbin; Shi, Peng

doi:10.1038/s41422-021-00517-6

Cited by 17 publications

(16 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous study, we have identi ed RETSAT as a convergent gene in high-altitude mammal species, emphasizing the contribution of RETSAT in mammalian hypoxia adaptation 32 . Here we report its functions in pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 98%

“…For instance, RETSAT protects broblasts from ultra violet (UV) or paraquat induced oxidative stress 31 , indicating unknown functions of RETSAT in oxidative homeostasis, or even UV induced DNA damage response and genomic stability. Using evolutionary genome comparison, we identi ed RETSAT to be a convergent gene in mammalian adaptation to hypoxia on the Qinghai-Tibetan Plateau, and the amino acid switch from glutamine (Q) to arginine (R) at the position 247 (Q247R) of RETSAT is responsible for heart function enhancement and mammalian adaptation to hypoxia 32 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma

Liu

Yao

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Severe hypoxia is a prominent character of pancreatic ductal adenocarcinoma (PDAC) microenvironment. In the process of gemcitabine based chemotherapy, PDAC cells are insulted from replication stresses co-induced by hypoxia and gemcitabine. However, PDAC cells get outstanding abilities to resist to such harsh conditions and keep proliferating, causing a major obstacle for current therapy. RETSAT (Retinol Saturase) is defined as a hypoxia convergent gene recently, with high expression in PDAC hypoxic sectors. This study aimed to explore the roles of RETSAT in replication stress resistance and hypoxia adaptation in PDAC cells, and decipher the underlying mechanism. Methods: The expression of RETSAT was examined in TCGA (The Cancer Genome Atlas), human pancreatic cancer microarray, clinical specimens and cell lines. Functions of RETSAT were studied by means of DNA fiber assay and comet assay in monolayer cultured PDAC cell lines, three dimensional spheroids, patient derived organoids and cell derived xenograft mouse models. Mechanism was investigated by using iPOND (isolate proteins on nascent DNA) combined with mass spectrometry, immunoprecipitation and immunoblotting. Results: First, we found the converse relationship of RETSAT expression and PDAC chemotherapy. That is, PDAC patients with high RETSAT expression correlated with poor survival, while ones holding low RETSAT expression were benefitted more in Gemcitabine based chemotherapy. Second, we identified RETSAT as a novel replication fork associated protein. HIF-1α signaling promotes RETSAT expression under hypoxia. Functionally, RETSAT promoted fork restarting under replication stress and maintained genomic stability. Third, we uncovered the interaction of RETSAT and R-loop unwinding helicase DDX39B. RETSAT detained DDX39B on forks to resolve R-loops, through which avoided fork damage and CHK1 initiated apoptosis. Targeting DDX39B using chemical CCT018159 sensitized PADC cells and organoids to gemcitabine induced apoptosis, highlighting the synergetic application of CCT018159 and gemcitabine in PDAC chemotherapy. Conclusion: This study identified RETSAT as a novel replication fork protein, which functions through interacting with DDX39B mediated R-loop clearance to promote fork restarting, leading to cellular resistance to replication stresses co-induced by tumor environmental hypoxia and gemcitabine in pancreatic ductal adenocarcinoma.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma

Liu

Yao

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our group has recently developed multiple comprehensive integrative bioinformatics methodologies to identify new biomarkers involved in hypoxic solid tumor progression. 15 , 40 – 42 Among the candidate tumor related new biomarkers, MrgprF, a MAS related GPR family member, was revealed to be downregulated in CM due to the hypermethylation in its promoter region, which could be reversed by 5-Azacytidine treatment, a well-known anti-cancer drug. 43 , 44 Consistently, 5-Azacytidine has previously been shown to behave as an anti-neoplastic agent for B16 melanoma.…”

Section: Discussionmentioning

confidence: 99%

MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K/Akt signaling

Shen

Han

et al. 2022

Sig Transduct Target Ther

Self Cite

View full text Add to dashboard Cite

The incidence of cutaneous melanoma (CM) has been increasing annually worldwide. In this study, we identify that MrgprF, a MAS related GPR family member, is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region, and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome. We demonstrate that MrgprF forced expression inhibits tumor cell proliferation, migration, xenograft tumor growth, and metastasis. On the contrary, MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells, supporting the inhibitory role of MrgprF during tumor progression. Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase (PI3K) complex formation between p101 and p110γ subunits, the critical step for phosphatidylinositol-(3, 4)-P2 (PIP2) conversion to phosphatidylinositol-(3, 4, 5)-P3 (PIP3), and then reduces the activation of PI3K/Akt signaling. This effect can be reversed by Akt specific agonist SC79. In addition, AMG 706, a previously documented inhibitor for endothelial cell proliferation, is identified as a potential agonist for MrgprF, and can impede tumor growth both in vitro and in vivo. Taken together, our findings suggest that MrgprF, a novel tumor suppressor in cutaneous melanoma, may be useful as a therapeutic target in the future.

show abstract

“…In our previous study, we have identified RETSAT as a convergent gene in high-altitude mammal species, emphasizing the contribution of RETSAT in mammalian hypoxia adaptation [ 32 ]. Here we report its functions in pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, RETSAT protects fibroblasts from ultra violet (UV) or paraquat induced oxidative stress [ 31 ], indicating unknown functions of RETSAT in oxidative homeostasis, or even UV induced DNA damage response and genomic stability. Using evolutionary genome comparison, we identified RETSAT to be a convergent gene in mammalian adaptation to hypoxia on the Qinghai-Tibetan Plateau, and the amino acid switch from glutamine (Q) to arginine (R) at the position 247 (Q247R) of RETSAT is responsible for heart function enhancement and mammalian adaptation to hypoxia [ 32 ]. RETSAT mutation is correlated to occurrence of undifferentiated tongue sarcoma [ 33 ], and its expression is positively associated with tumor immune infiltration [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma

Liu

Yao

et al. 2022

J Exp Clin Cancer Res

Self Cite

View full text Add to dashboard Cite

Background Severe hypoxia is a prominent character of pancreatic ductal adenocarcinoma (PDAC) microenvironment. In the process of gemcitabine based chemotherapy, PDAC cells are insulted from replication stresses co-induced by hypoxia and gemcitabine. However, PDAC cells get outstanding abilities to resist to such harsh conditions and keep proliferating, causing a major obstacle for current therapy. RETSAT (Retinol Saturase) is defined as a hypoxia convergent gene recently, with high expression in PDAC hypoxic sectors. This study aimed to explore the roles of RETSAT in replication stress resistance and hypoxia adaptation in PDAC cells, and decipher the underlying mechanism. Methods The expression of RETSAT was examined in TCGA (The Cancer Genome Atlas), human pancreatic cancer microarray, clinical specimens and cell lines. Functions of RETSAT were studied by means of DNA fiber assay and comet assay in monolayer cultured PDAC cell lines, three dimensional spheroids, patient derived organoids and cell derived xenograft mouse models. Mechanism was investigated by using iPOND (isolate proteins on nascent DNA) combined with mass spectrometry, immunoprecipitation and immunoblotting. Results First, we found the converse relationship of RETSAT expression and PDAC chemotherapy. That is, PDAC patients with high RETSAT expression correlated with poor survival, while ones holding low RETSAT expression were benefitted more in Gemcitabine based chemotherapy. Second, we identified RETSAT as a novel replication fork associated protein. HIF-1α signaling promotes RETSAT expression under hypoxia. Functionally, RETSAT promoted fork restarting under replication stress and maintained genomic stability. Third, we uncovered the interaction of RETSAT and R-loop unwinding helicase DDX39B. RETSAT detained DDX39B on forks to resolve R-loops, through which avoided fork damage and CHK1 initiated apoptosis. Targeting DDX39B using chemical CCT018159 sensitized PDAC cells and organoids to gemcitabine induced apoptosis, highlighting the synergetic application of CCT018159 and gemcitabine in PDAC chemotherapy. Conclusions This study identified RETSAT as a novel replication fork protein, which functions through interacting with DDX39B mediated R-loop clearance to promote fork restarting, leading to cellular resistance to replication stresses co-induced by tumor environmental hypoxia and gemcitabine in pancreatic ductal adenocarcinoma.

show abstract

A single mutation underlying phenotypic convergence for hypoxia adaptation on the Qinghai-Tibetan Plateau

Cited by 17 publications

References 13 publications

RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma

RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma

MrgprF acts as a tumor suppressor in cutaneous melanoma by restraining PI3K/Akt signaling

RETSAT associates with DDX39B to promote fork restarting and resistance to gemcitabine based chemotherapy in pancreatic ductal adenocarcinoma

Contact Info

Product

Resources

About