ABSTRACT
C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.
ABSTRACT
Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.
ABSTRACT
Global changes caused by the increases of atmospheric CO2 concentration and temperature have important effects on soil biogeochemical processes. The synthesis and release of volatile halogenated organic compounds (VOXs) is an important pathway for soil to participate in the global material cycle and energy flow. In this study, Schima superba and Cunninghamia lanceolata seedlings in the southern subtropics were selected as the research objects. Four treatments, including control (CK), elevated CO2 concentration (EC), elevated temperature (ET) and elevated both factors (EC+ET) were set up. The effects of EC and ET on soil VOXs formation were studied by an open-top chamber system coupled with a purging and trapping gas chromatography/mass spectrometry. The results showed that VOXs content in the soil of S. superba seedlings was 0.065-0.252 ng·g-1, which was higher than that of C. lanceolata (0.038-0.136 ng·g-1). At the EC, ET and EC+ET treatments, VOXs contents were reduced in soils of both species. The effect of ET was the most significant, with the decrease rates of 74.2% and 72.1% in both soils, respectively. The change of VOXs content with increasing temperature mainly attributed to the changes of soil moisture and nitrogen content. The content of VOXs in the soils of S. superba seedlings decreased more than that of C. lanceolata under different treatments. In CK, EC, ET and EC+ET treatment, bromodichloromethane (BDCM) (27.5%, 36.7%, 32.9%, 32.6%) and tetrachloromethane (TCM) (9.0%, 16.8%, 22.7%, 15.8%) were the main VOXs in the soil of S. superba seedlings, respectively, while BDCM and dibromomethane (DBM) were the main VOXs in the soil of C. lanceolata seedlings. BDCM accounted for 31.9%, 38.2%, 40.9% and 37.2% of the VOXs content in each treatment, and DBM accounted for 17.9%, 16.5%, 19.2% and 16.0% of the VOXs content, respectively. Simulating elevated atmospheric CO2 concentration and temperature was conducive to more comprehensive reflection of the ecological effect of global climate change, and it could provide data support for improving the VOCs flux model.