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Background Posttranslational modifications (PTMs) play critical roles in hepatocellular carcinoma (HCC). However, the locations of PTM-modified sites across protein secondary structures and regulatory patterns in HCC remain largely uncharacterized. Methods Total proteome and nine PTMs (phosphorylation, acetylation, crotonylation, ubiquitination, lactylation, N-glycosylation, succinylation, malonylation, and β-hydroxybutyrylation) in tumor sections and paired normal adjacent tissues derived from 18 HCC patients were systematically profiled by 4D-Label free proteomics analysis combined with PTM-based peptide enrichment. Results We detected robust preferences in locations of intrinsically disordered protein regions (IDRs) with phosphorylated sites and other site biases to locate in folded regions. Integrative analyses revealed that phosphorylated and multiple acylated-modified sites are enriched in proteins containing RRM1 domain, and RNA splicing is the key feature of this subset of proteins, as indicated by phosphorylation and acylation of splicing factor NCL at multiple residues. We confirmed that NCL-S67, K398, and K646 cooperate to regulate RNA processing. Conclusion Together, this proteome profiling represents a comprehensive study detailing regulatory patterns based on multiple PTMs of HCC.

DSBs can arise from the exposure to exogenous agents, such as ultraviolet (UV) light from the sun, ionizing radiation (IR), carcinogens that are inhaled or ingested, and certain genotoxic chemicals, as well as from some endogenous biological processes, including DNA replication stresses and reactive oxygen species (ROS) which is produced as a byproduct of normal cellular metabolism. Like many other types of cancers, defects in DSBs repair and increased genome instability may contribute to the tumorigenesis and development of HCC. [...]it is of high significance for the depth study of the mechanisms of DSBs repair in HCC. [...]it is reported that DDB1 could interact with PARP1 upon UV damage and DDB1 was a target for PARP-mediated PARylation. See PDF.] DDB1 is PARylated in response to DNA damage and the inhibition of PARG impairs DSBs repair in HCC. a Coverage and peptides number of PARylated DDB1 detected by LC–MS. b The Hep3B cells were lysed and immunoprecipitated with Af1521 macrodomain (PAR/MAR) affinity resins or an anti-DDB1 antibody followed by western blotting with an anti-DDB1 antibody or an anti-PAR antibody at the indicated time points after X-Ray treatment (4 Gy). c Colony-formation assays were applied to assess the survival of Hep3B and HCCLM3 cells treated with X-Ray (1 Gy), with PARG inhibitor (1 μM). d Western blotting assays for the effect of PARG inhibition (2 μM PDD00017273) on the γH2AX expression level in Hep3B and HCCLM3 cells at the indicated time points after X-Ray treatment (4 Gy) The endogenous PARG levels of different HCC cell lines using quantitative RT-PCR and western blot indicated that PARG was highly expressed in Hep3B and HCCLM3 HCC cell lines [5].

Sinusoidal dedifferentiation is a complicated process induced by several factors, and exists in early stage of diverse liver diseases. The mechanism of sinusoidal dedifferentiation is poorly unknown. In this study, we established a NaAsO 2 -induced sinusoidal dedifferentiation mice model. Liver sinusoidal endothelial cells were isolated and isobaric tag for relative and absolute quantitation (iTRAQ) based proteomic approach was adopted to globally examine the effects of arsenic on liver sinusoidal endothelial cells (LSECs) during the progression of sinusoidal dedifferentiation. In all, 4205 proteins were identified and quantified by iTRAQ combined with LC-MS/MS analysis, of which 310 proteins were significantly changed in NaAsO 2 group, compared with the normal control. Validation by western blot showed increased level of clathrin-associated sorting protein Disabled 2 (Dab2) in NaAsO 2 group, indicating that it may regulate receptor endocytosis, which served as a mechanism to augment intracellular VEGF signaling. Moreover, we found that knockdown of Dab2 reduced the uptake of VEGF in LSECs, furthermore blocking VEGF-mediated LSEC dedifferentiation and angiogenesis.

Background Metabolic disorder is an essential characteristic of tumor development. Ketogenesis is a heterogeneous factor in multiple cancers, but the effect of ketogenesis on hepatocellular carcinoma (HCC) is elusive. Methods We aimed to explain the role of ketogenesis-related hydroxy-methyl-glutaryl-CoA lyase (HMGCL) on HCC suppression. Expression pattern of HMGCL in HCC specimens was evaluated by immunohistochemistry (IHC). HMGCL was depleted or overexpressed in HCC cells to investigate the functions of HMGCL in vitro and in vivo. The anti-tumor function of HMGCL was studied in subcutaneous xenograft and Trp53 Δhep/Δhep ; c-Myc -driven HCC mouse models. The mechanism of HMGCL-mediated tumor suppression was studied by IHC, western blot (WB) and Cut & Tag. Results HMGCL depletion promoted HCC proliferation and metastasis, whereas its overexpression reversed this trend. As HMGCL catalyzes β-hydroxy-butyric acid (β-OHB) production, we discovered that HMGCL increased acetylation at histone H3K9, which further promoted the transcription of dipeptidyl peptidase 4 (DPP4), a key protein maintains intracellular lipid peroxidation and iron accumulation, leading to HCC cells vulnerability to erastin- and sorafenib-induced ferroptosis. Conclusion Our study identified a critical role of HMGCL on HCC suppression, of which HMGCL regulated H3K9 acetylation through β-OHB and modulating the expression of DPP4 in a dose-dependent manner, which led to ferroptosis in HCC cells.

Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.