T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Adult ; Female ; Humans ; Male ; Middle Aged ; Parotid Neoplasms ; diagnosis ; pathology ; surgery ; Retrospective Studies

BACKGROUND AND OBJECTIVERadiation usually results in paranasal sinusitis in patients with nasopharyngeal carcinoma (NPC), which influences patients' quality of life. This study aimed to determine the relationships between dose distribution in the nasal cavity and nasal mucous injury in patients with NPC treated by intensity-modulated radiation therapy (IMRT), and to find the tolerable radiation dose for the nasal mucous.

METHODSSixty-six patients with NPC treated by IMRT between October 2006 and November 2008 were enrolled. The irradiation dose in the nasal cavity was determined by the computer with the IMRT work platform. Mucociliary transport rate (MTR) was detected by modified saccharine test before IMRT, at the end of IMRT, and at 3, 6, and 12 months after IMRT.

RESULTSThe data were available for 129 nasal cavities. The cavities receiving a mean dose below or equal to 37 Gy showed substantial preservation of nasal mucous after IMRT. The MRT decreased to (62.82 ± 38.59)%, (56.78 ± 37.79)%, (64.05 ± 39.37)%, and (71.13 ± 39.55)% of pre-IMRT value at 4 time points after IMRT, with significant differences among the data (P < 0.05). In contrast, when the cavities received a mean dose higher than 37 Gy, no significant differences in MTR among the time points were observed. At 3 months after IMRT, the MTR was the lowest (38.27% of pre-RT value).

CONCLUSIONSA mean radiation dose of ≤ 37 Gy for the nasal cavity is an optimal dose to protect the nasal cavity function.

Adult ; Carcinoma, Squamous Cell ; physiopathology ; radiotherapy ; Female ; Humans ; Male ; Mucociliary Clearance ; radiation effects ; Nasal Cavity ; radiation effects ; Nasopharyngeal Neoplasms ; physiopathology ; radiotherapy ; Quality Control ; Radiotherapy Dosage ; Radiotherapy, Intensity-Modulated

OBJECTIVETo investigate the expression of ER alpha in chemically induced, ER alpha-negative human breast cancer MDA-MB-435 cells and its restoration of the responsiveness to endocrine therapy.

METHODSMDA-MB-435 cells were treated with HDAC inhibitor trichostatin A(TSA)and DNMT1 inhibitor 5-AZA-CdR (AZA). The mRNA level of ER alpha, PR and PS2 in treated MDA-MB-435 cells was detected by RT-PCR. The WST-8 (water-soluble tetrazolium salt-8) method was used to analyze the proliferation rate of the cells. Xenograft in female nude mice was used to further explore the change of proliferation rate of treated MDA-MB-435 cells in vivo.

RESULTSAfter treatment with AZA and TSA, mRNA expression of ER alpha, PR and pS2 was up-regulated in MDA-MB-435 cells. The mRNA level of ER alpha was the hightest when MDA-MB-435 cells were treated with 2.5 micromol/L AZA and 100 ng/ml TSA. The treated MDA-MB-435 cells showed different proliferation rate in various media containing different concentration of estrodial. The MDA-MB-435 cells showed down-regulated proliferation rate after treatment with the combination of 2.5 micromol/L AZA and 100 ng/ml TSA, and 4-OH tamoxifen could suppress the growth rate of the induced MD-MBA-435 cells but not the untreated cells. The treated MDA-MB-435 cells showed slower proliferation rate than that of untreated cells in vivo (P <0. 01), and the proliferation rate of the treated MDA-MB-435 cells became lower when the nude mice were deprived of estrogen by castration (P <0. 01).

CONCLUSIONAfter treatment with TSA and AZA, ER alpha-negative MDA-MB-435 cells can express functional ER alpha and regain responsiveness to estrogen both in vitro and in vivo. HDAC inhibitor and DNMT1 inhibitor may play an important role in restoration of sensitivity of ER alpha-negative breast cancers to endocrine therapy.

Animals ; Azacitidine ; analogs & derivatives ; pharmacology ; Breast Neoplasms ; genetics ; pathology ; prevention & control ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; DNA Modification Methylases ; antagonists & inhibitors ; Enzyme Inhibitors ; pharmacology ; Estrogen Receptor alpha ; genetics ; Female ; Gene Expression Regulation, Neoplastic ; drug effects ; Histone Deacetylase Inhibitors ; Humans ; Hydroxamic Acids ; pharmacology ; Mammary Neoplasms, Experimental ; genetics ; pathology ; prevention & control ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Ovariectomy ; RNA, Messenger ; biosynthesis ; genetics ; Receptors, Progesterone ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Trefoil Factor-1 ; Tumor Suppressor Proteins ; genetics ; Xenograft Model Antitumor Assays