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Abstract Background Hypoxia contributes to cancer progression through various molecular mechanisms and hepatocellular carcinoma (HCC) is one of the most hypoxic malignancies. Hypoxia-inducible gene domain protein-1a (HIGD1A) is typically induced via epigenetic regulation and promotes tumor cell survival during hypoxia. However, the role of HIGD1A in HCC remains unknown. Methods HIGD1A expression was determined in 24 pairs of human HCC samples and para-tumorous tissues. Loss-of-function experiments were conducted both in vivo and in vitro to explore the role of HIGD1A in HCC proliferation and metastasis. Results Increased HIGD1A expression was found in HCC tissues and cell lines, which was induced by hypoxia or low-glucose condition. Moreover, HIGD1A knockdown in HCC cells arrested the cell cycle at the G2/M phase and promoted hypoxia-induced cell apoptosis, resulting in great inhibition of cell proliferation, migration, and invasion, as well as tumor xenograft formation. Interestingly, these anti-tumor effects were not observed in normal hepatocyte cell line L02. Further, HIGD1A knockdown suppressed the expression of ornithine decarboxylase 1 (ODC1), a rate-limiting enzyme of polyamine metabolism under c-Myc regulation. HIGD1A was found to bind with the c-Myc promoter region, and its knockdown decreased the levels of polyamine metabolites. Consistently, the inhibitory effect on HCC phenotype by HIGD1A silencing could be reversed by overexpression of c-Myc or supplementation of polyamines. Conclusions Our results demonstrated that HIGD1A activated c-Myc–ODC1 nexus to regulate polyamine synthesis and to promote HCC survival and malignant phenotype, implying that HIGD1A might represent a novel therapeutic target for HCC.

Background: Hypoxia contributes to cancer progression through various molecular mechanisms and hepatocellular carcinoma (HCC) is one of the most hypoxic malignancies. Hypoxia-inducible gene domain protein-1a (HIGD1A) is typically induced via epigenetic regulation and promotes tumor cell survival during hypoxia. However, the role of HIGD1A in HCC remains unknown. Methods: HIGD1A expression was determined in 24 pairs of human HCC samples and para-tumorous tissues. Loss-of-function experiments were conducted both in vivo and in vitro to explore the role of HIGD1A in HCC proliferation and metastasis. Results: Increased HIGD1A expression was found in HCC tissues and cell lines, which was induced by hypoxia or low-glucose condition. Moreover, HIGD1A knockdown in HCC cells arrested the cell cycle at the G2/M phase and promoted hypoxia-induced cell apoptosis, resulting in great inhibition of cell proliferation, migration, and invasion, as well as tumor xenograft formation. Interestingly, these anti-tumor effects were not observed in normal hepatocyte cell line L02. Further, HIGD1A knockdown suppressed the expression of ornithine decarboxylase 1 (ODC1), a rate-limiting enzyme of polyamine metabolism under c-Myc regulation. HIGD1A was found to bind with the c-Myc promoter region, and its knockdown decreased the levels of polyamine metabolites. Consistently, the inhibitory effect on HCC phenotype by HIGD1A silencing could be reversed by overexpression of c-Myc or supplementation of polyamines. Conclusions: Our results demonstrated that HIGD1A activated c-Myc–ODC1 nexus to regulate polyamine synthesis and to promote HCC survival and malignant phenotype, implying that HIGD1A might represent a novel therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Curcumin is the active ingredient of Curcuma longa, which inhibits the development of malignant cells. Prevention and treatment of cancer by natural compounds, especially curcumin, and understanding the mechanism of action, is an area of interest in cancer research. In this study, we evaluated the effects of curcumin on cell proliferation, ornithine decarboxylase 1 (ODC1) and adenosine deaminase (ADA) gene expression in human breast cancer cell line (MCF-7) as compared to the non-cancer line (MCF-10A). Both cell lines were subjected to increasing doses of curcumin, ranging from 0 to 30 μg/mL. Cell viability was quantified by the MTT assay. In vitro clonogenic survival assay was performed on MCF-7 cells. Expression of ADA and ODC1 were analyzed by Western blotting and qRT-PCR. Curcumin inhibited the growth of malignant cells in a time- and dose-dependent manner. The calculated IC50 value for MCF-7 cells in 48 h was 12 μg/mL. Forty-five to 70% decreases in colony formation were observed in MCF-7 cells treated with 30-60 μg/mL curcumin, respectively. Our data revealed a dose-dependent downregulation of ODC1 and ADA expression and respective enzyme activities by curcumin, which correlated with decreased proliferation in the MCF-7 breast cancer cell line. These data suggest that curcumin represses the proliferation of breast cancer cells through downregulation of ODC1 and ADA gene expression, which might be another mechanism of curcumin-mediated tumor growth inhibition.

Polyamines serve a number of vital functions in humans, including regulation of cellular proliferation, intracellular signaling, and modulation of ion channels. Ornithine decarboxylase 1 (ODC1) is the rate‐limiting enzyme in endogenous polyamine synthesis. In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain‐of‐function variants in the ODC1 gene. This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow–Robin spaces, periventricular cysts, and abnormalities of the corpus callosum. Plasma clinical metabolomics analysis demonstrates elevation of N‐acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels. Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease‐modifying therapies. As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder. [ABSTRACT FROM AUTHOR]

Highlights: [•] Evidence supports both heritable and environmental influences in depression and suicidal behavior risk. [•] Gene–environment interaction (G×E) studies may be useful to investigate the impact of both sources of risk. [•] So far, within this context, only few results have been obtained in both depression and suicidal behavior, though some genes seems reliably moderating the environmental risk for these disturbances. [•] However, traditional G×E studies suffer from a nr of limitations, therefore novel methods of investigation are required to overcome current G×E studies’ pitfalls. [ABSTRACT FROM AUTHOR]