Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma.

Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy.

The modulation of PD-L1 induced by the oncogenic HBXIP for breast cancer growth.

Programmed death ligand-1 (PD-L1)/PD-1 checkpoint extensively serves as a central mediator of immunosuppression. A tumor-promoting role for abundant PD-L1 in several cancers is revealed. However, the importance of PD-L1 and how the PD-L1 expression is controlled in breast cancer remains obscure. Here, the mechanisms of controlling PD-L1 at the transcription and protein acetylation levels in promoting breast cancer growth are presented. Overexpressed PD-L1 accelerates breast cancer growth in vitro and in vivo. RNA-seq uncovers that PD-L1 can induce some target genes affecting many cellular processes, especially cancer development. In clinical breast cancer tissues and cells, PD-L1 and HBXIP are both increased, and their expressions are positively correlated. Mechanistic exploration identifies that HBXIP stimulates the transcription of PD-L1 through co-activating ETS2. Specifically, HBXIP induces PD-L1 acetylation at K270 site through interacting with acetyltransferase p300, leading to the stability of PD-L1 protein. Functionally, depletion of HBXIP attenuates PD-L1-accelerated breast tumor growth. Aspirin alleviates breast cancer via targeting PD-L1 and HBXIP. Collectively, the findings display new light into the mechanisms of controlling tumor PD-L1 and broaden the utility for PD-L1 as a target in breast cancer therapy.

[Effects of water-nitrogen interaction on the contents and components of protein and starch in wheat grains].

With wheat cultivars Yumai 34 (strong-gluten wheat) and Yumai 50 (weak-gluten wheat) as test materials, a field experiment was conducted to study the effects of three irrigation treatments (irrigation at jointing stage, at jointing and grain-filling stages, and at jointing, grain-filling, and pre-maturing stages), three nitrogen application rates (0, 150, and 270 kg x hm(-2)), and their combinations on the contents and components of protein and starch in wheat grains. The results showed that for strong-gluten wheat cultivar Yumai 34, applying 270 kg x hm(-2) of N increased the total content of protein and the contents of albumin, gliadin and glutelin, and enhanced the glutelin/gliadin ratio. This application rate of nitrogen also increased the total content of starch and the content of amylopectin, and decreased the amylose/amylopetin ratio. For weak-gluten wheat cultivar Yumai 50, applying 150 kg x hm(-2) of N increased the contents of albumin and gliadin, and decreased the contents of globulin and glutelin and the glutelin/gliadin ratio. The amylopectin and starch contents also increased when the N application rate was 150 kg x hm(-2). Non-N fertilization or applying 270 kg x hm(-2) of N decreased the accumulation of protein and starch, and resulted in a decrease of grain yield. Among the irrigation treatments, irrigation at jointing and grain-filling stages promoted the accumulation of protein and starch in grains and increased the grain yield, while the other two treatments were unbeneficial to the accumulation of protein and starch and decreased the grain yield. Applying 270 kg x hm(-2) and 150 kg x hm(-2) of N combined with irrigation at jointing and grain-filling stages was the ideal management regime for the high yield and good quality of strong- and weak-gluten wheat cultivars, respectively.