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Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting step in hepatic gluconeogenesis pathway to maintain blood glucose levels. Mammalian cells express two PCK genes, encoding for a cytoplasmic (PCPEK-C or PCK1) and a mitochondrial (PEPCK-M or PCK2) isoforms, respectively. Increased expressions of both PCK genes are found in cancer of several organs, including colon, lung and skin, and linked to increased anabolic metabolism and cell proliferation. Here, we report that the expressions of both PCK1 and PCK2 genes are downregulated in primary hepatocellular carcinoma (HCC) and low PCK expression was associated with poor prognosis in patients with HCC. Forced expression of either PCK1 or PCK2 in liver cancer cell lines results in severe apoptosis under the condition of glucose deprivation and suppressed liver tumorigenesis in mice. Mechanistically, we show that the proapoptotic effect of PCK1 requires its catalytic activity. We demonstrate that forced PCK1 expression in glucose-starved liver cancer cells induced TCA cataplerosis, leading to energy crisis and oxidative stress. Replenishing TCA intermediate α-ketoglutarate or inhibition of reactive oxygen species production blocked the cell death caused by PCK expression. Taken together, our data reveal that PCK1 is detrimental to malignant hepatocytes and suggest activating PCK1 expression as a potential treatment strategy for patients with HCC.

Peroxisomes account for ~35% of total HO generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid β-oxidation and a major producer of HO ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases HO production and oxidative DNA damage, which can be alleviated by knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.

A series of single-composition emission-tunable Ca9Y(PO4)7:Eu2+,Mn2+ phosphors were synthesized by solid-state reaction. The energy transfer from Eu2+ to Mn2+ in Ca9Y(PO4)7 host matrix was studied and demonstrated to be a resonant type via a dipole−quadrupole mechanism with the critical distance of ∼ 11 Å. The wavelength-tunable white light can be realized by coupling the emission bands centered at 486 and 638 nm ascribed to the contribution from Eu2+ and Mn2+, respectively. By properly tuning the relative composition of Eu2+/Mn2+, chromaticity coordinates of (0.31, 0.33) can be achieved under excitation at 250−440 nm. Moreover, white-light-emitting diodes were fabricated through the integration of 365 nm chips and single composition white-light-emitting phosphors (Ca0.975Eu0.01Mn0.015)9Y(PO4)7 into a single package shows a cool white light of 7200 K, color rendering index of 76, and color coordinates of (0.30, 0.31) close to that of ideal white light can be achieved.

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Single-phased white-light-emitting phosphors Ca 9 Gd(PO 4 ) 7 :Eu 2+ ,Mn 2+ were synthesized by solid state reactions. Tuning the Eu 2+ /Mn 2+ ratio via the energy transfer varied the emission hue of Ca 9 Gd(PO 4 ) 7 :0.007Eu 2+ ,xMn 2+ from blue-greenish (0.219, 0.371) to white-light (0.326, 0.328) and eventually to red (0.625, 0.307). The mechanism of transferring energy from a sensitizer Eu 2+ to an activator Mn 2+ in Ca 9 Gd(PO 4 ) 7 :Eu 2+ ,Mn 2+ phosphors was demonstrated to be an electric dipole-quadrupole interaction. Combining a near-UV 380 nm chip and a white-emitting Ca 9 Gd(PO 4 ) 7 :0.007Eu 2+ ,0.02Mn 2+ phosphor produced a white-light near-UV LED, demonstrating CIE chromaticity coordinates of (0.312, 0.327) and a color temperature of 6569 K.

Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacological inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity and other diseases. Here we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin-ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy.