Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. However, the underlying mechanism is unclear. Herein, we report the role of lymphoid-specific helicase (LSH), a chromatin-remodeling protein, in suppressing erastin-induced ferroptosis in CRC cells. We demonstrate that erastin treatment leads to dose- and time-dependent downregulation of LSH in CRC cells, and depletion of LSH increases cell sensitivity to ferroptosis. Mechanistically, LSH interacts with and is stabilized by ubiquitin-specific protease 11 (USP11) via deubiquitination; this interaction was disrupted by erastin treatment, resulting in increased ubiquitination and LSH degradation. Moreover, we identified cytochrome P450 family 24 subfamily A member 1 (CYP24A1) as a transcriptional target of LSH. LSH binds to the CYP24A1 promoter, promoting nucleosome eviction and reducing H3K27me3 occupancy, thus leading to transcription of CYP24A1. This cascade inhibits excessive intracellular Ca2+ influx, thereby reducing lipid peroxidation and ultimately conferring resistance to ferroptosis. Importantly, aberrant expression of USP11, LSH, and CYP24A1 is observed in CRC tissues and correlates with poor patient prognosis. Taken together, our study demonstrates the crucial role of the USP11/LSH/CYP24A1 signaling axis in inhibiting ferroptosis in CRC, highlighting its potential as a therapeutic target in CRC treatment.

AimsAs sex hormone-dependent tumors, it remains to be clarified whether there is a common genetic signature and its value between breast and endometrial cancers. The aim of this study was to establish the shared sex hormone metabolism-related gene prognostic index (SHMRGPI) between breast and endometrial cancers and to analyze its potential role in the therapeutic and prognostic assessment of endometrial cancers.MethodsUsing transcriptome data from TCGA, tumor-associated gene modules were identified by weighted gene co-expression network analysis, and the intersection of module genes with female sex hormone synthesis and metabolism genes was defined as sex hormone metabolism-related gene. SHMRGPI was established by the least absolute shrinkage and selection operator and Cox regression. Its prognostic value of patients with endometrial cancer was validated, and a nomogram was constructed. We further investigated the relationship between SHMRGPI groups and clinicopathological features, immune infiltration, tumor mutation burden, and drug sensitivity.ResultsA total of 8 sex hormone metabolism-related gene were identified as key genes for the construction of prognostic models. Based on SHMRGPI, endometrial cancer patients were divided into high and low SHMRGPI groups. Patients in the low SHMRGPI group had longer overall survival (OS) compared with the high group (P< 0.05). Furthermore, we revealed significant differences between SHMRGPI groups as regards tumor immune cell infiltration, somatic mutation, microsatellite instability and drug sensitivity. Patients with low SHMRGPI may be the beneficiaries of immunotherapy and targeted therapy.ConclusionsThe SHMRGPI established in this study has prognostic power and may be used to screen patients with endometrial cancer who may benefit from immunotherapy or targeted therapy.

AimsThe findings in epidemiological studies suggest that endometrioid endometrial cancer (EEC) is associated with obesity. However, evidence from gene expression data for the relationship between the two is still lacking. The purpose of this study was to explore the merits of establishing an obesity-related genes (ORGs) signature in the treatment and the prognostic assessment of EEC.MethodsMicroarray data from GSE112307 were utilized to identify ORGs by using weighted gene co-expression network analysis. Based on the sequencing data from TCGA, we established the prognostic ORGs signature, confirmed its value as an independent risk factor, and constructed a nomogram. We further investigated the association between grouping based on ORGs signature and clinicopathological characteristics, immune infiltration, tumor mutation burden and drug sensitivity.ResultsA total of 10 ORGs were identified as key genes for the construction of the signature. According to the ORGs score computed from the signature, EEC patients were divided into high and low-scoring groups. Overall survival (OS) was shorter in EEC patients in the high-scoring group compared with the low-scoring group (P < 0.001). The results of the Cox regression analysis showed that ORGs score was an independent risk factor for OS in EEC patients (HR = 1.017, 95% confidence interval = 1.011–1.023; P < 0.001). We further revealed significant disparities between scoring groups in terms of clinical characteristics, tumor immune cell infiltration, and tumor mutation burden. Patients in the low-scoring group may be potential beneficiaries of immunotherapy and targeted therapies.ConclusionsThe ORGs signature established in this study has promising prognostic predictive power and may be a useful tool for the selection of EEC patients who benefit from immunotherapy and targeted therapies.

BRCA1 plays a suppressive role in breast tumorigenesis. Ubiquitin-dependent degradation is a common mechanism that regulates BRCA1 protein stability, and several ubiquitin ligases involved have been identified. However, the deubiquitinating enzyme for BRCA1 remains less defined. Here, we report that the deubiquitinase USP4 interacts with, deubiquitinates and stabilizes BRCA1, maintaining the protein level of BRCA1. USP4 knockdown results in a decreased BRCA1 protein level, impairment in homologous recombination mediated double-stranded break repair, and increased genome instability, and confers resistance to DNA damage-inducing agents and PARP inhibitors. Ectopic expression of USP4 stabilizes BRCA1 and reverse the effects caused by USP4 knockdown. Moreover, USP4 is low expressed in human breast cancer tissues and its low expression correlates with poorer survival of patients. Furthermore, we identified several loss-of-function mutations of USP4 in human gynecological cancers, the catalytic activity of which or their interaction with BRCA1 is disrupted. Together, we reveal that USP4 is a deubiquitinase for BRCA1. USP4 positively regulates the stability and function of BRCA1 through deubiquitination, and plays important role in the suppression of breast cancer.