HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway.

Esophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown. Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells. Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway. HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT. Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted therapy.

Liu MJ ，Zhao Y ，Li QT ，Lei XY ，He KY ，Guo JR ，Yang JY ，Yan ZH ，Wu DH ，Zhang L ，Jian YP ，Xu ZX ... -  《Cell Death & Disease》

HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis.

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Yang JY ，Lei XY ，He KY ，Guo JR ，Liu MJ ，Li JQ ，Li QT ，Jiang ZH ，Zhang L ，Wu DH ，Li YJ ，Sun QH ，Jian YP ，Xu ZX ... -  《-》

Fra-1 Regulates the Expression of HMGA1, Which is Associated with a Poor Prognosis in Human Esophageal Squamous Cell Carcinoma.

Toyozumi T ，Hoshino I ，Takahashi M ，Usui A ，Akutsu Y ，Hanari N ，Murakami K ，Kano M ，Akanuma N ，Suitoh H ，Matsumoto Y ，Sekino N ，Komatsu A ，Matsubara H ... -  《-》

CircDUSP16 Contributes to Cell Development in Esophageal Squamous Cell Carcinoma by Regulating miR-497-5p/TKTL1 Axis.

The vital roles of circular RNAs in human cancers have been demonstrated. In this study, we aimed to investigate the functions of circDUSP16 in esophageal squamous cell carcinoma (ESCC) development. Quantitative real-time polymerase chain reaction was executed for the expression levels of circDUSP16, DUSP16, miR-497-5p, and transketolase-like-1 (TKTL1) messenger RNA. Actinomycin D assay and RNase R digestion assay were used to determine the characteristics of circDUSP16. Cell Counting Kit-8 assay and colony formation assay were applied for cell proliferation. Transwell assay was performed to assess cell migration and invasion. The glycolysis level was evaluated using specific kits. Protein levels were measured by Western blot assay. RNA pull-down assay and dual-luciferase reporter assay were adopted to explore the relationships among circDUSP16, miR-497-5p, and TKTL1. Murine xenograft model was used to determine the role of circDUSP16 in ESCC in vivo. CircDUSP16 level was elevated in ESCC tissues, cells, and hypoxia-stimulated ESCC cells. Knockdown of circDUSP16 suppressed hypoxia-induced ESCC cell viability, colony formation, migration, invasion, and glycolysis. For mechanism analysis, circDUSP16 could positively regulate TKTL1 expression by sponging miR-497-5p in ESCC cells. Moreover, miR-497-5p inhibition restored the effects of circDUSP16 knockdown on the malignant behaviors of ESCC cells under hypoxia condition. MiR-497-5p overexpression suppressed hypoxia-induced ESCC cell progression by targeting TKTL1. In addition, circDUSP16 knockdown repressed the tumorigenesis of ESCC in vivo. CircDUSP16 knockdown suppressed hypoxia-induced ESCC cell growth, invasion, and glycolysis by regulating TKTL1 expression through sponging miR-497-5p.

Ma L ，Li H ，Lin Y ，Wang G ，Xu Q ，Chen Y ，Xiao K ，Rao X ... -  《-》

Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid-induced cancer development.

Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC-DR, established from a metastatic thoracic lesion. ESCC-DRtca2M was prepared by treating ESCC-DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose-6-phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF-κB) (p65) and O-linked N-Acetylglucosamine (O-GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O-GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line-based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF-κB (p65) and O-GlcNAc were expressed more highly in ESCC-DRtca2M than in the other cell lines. Moreover, ESCC-DRtca2M cells had additional chromosomal abnormalities in excess of ESCC-DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF-κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line-based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF-κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.

Munemoto M ，Mukaisho KI ，Miyashita T ，Oyama K ，Haba Y ，Okamoto K ，Kinoshita J ，Ninomiya I ，Fushida S ，Taniura N ，Sugihara H ，Fujimura T ... -  《-》