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Supplementary Data from SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation–Phosphorylation Cross-talk

Supplementary Table from SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation–Phosphorylation Cross-talk

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy.Significance:SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy.This article is highlighted in the In This Issue feature, p. 2007

Activating signal co-integrator complex (ASCC) supports diverse genome maintenance and gene expression processes. Its ASCC3 subunit is an unconventional nucleic acid helicase, harboring tandem Ski2-like NTPase/helicase cassettes crucial for ASCC functions. Presently, the molecular mechanisms underlying ASCC3 helicase activity and regulation remain unresolved. Here, we present cryogenic electron microscopy, DNA-protein cross-linking/mass spectrometry as well as in vitro and cellular functional analyses of the ASCC3-ASC1/TRIP4 sub-module of ASCC. Unlike the related spliceosomal SNRNP200 RNA helicase, ASCC3 can thread substrates through both helicase cassettes. ASC1 docks on ASCC3 via a zinc finger domain and stimulates the helicase by positioning a C-terminal ASC1-homology domain next to the C-terminal helicase cassette of ASCC3, likely assisting the DNA exit. ASC1 binds ASCC3 mutually exclusively with the DNA/RNA dealkylase, ALKBH3, directing ASCC for specific processes. Our findings define ASCC3-ASC1/TRIP4 as a tunable motor module of ASCC that encompasses two cooperating ATPase/helicase units functionally expanded by ASC1/TRIP4.

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy. Significance: SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007

Background and Objectives: The purpose of the present study was to elucidate the in-hospital and long-term outcomes of patients with head and neck cancer (HNC) bleeding and to analyze the risk factors for mortality. Materials and Methods: We included patients who presented to the emergency department (ED) with HNC bleeding. Variables of patients who survived and died were compared and associated factors were investigated by logistic regression and Cox’s proportional hazard model. Results: A total of 125 patients were enrolled in the present study. Fifty-nine (52.8%) patients experienced a recurrent bleeding event. The in-hospital mortality rate was 16%. The overall survival at 1, 3 and 5 years was 48%, 41% and 34%, respectively. The median survival time was 9.2 months. Multivariate logistic regression analyses revealed that risk factors for in-hospital mortality were inotropic support (OR = 10.41; Cl 1.81–59.84; p = 0.009), hypopharyngeal cancer (OR = 4.32; Cl 1.29–14.46; p = 0.018), and M stage (OR = 5.90; Cl 1.07–32.70; p = 0.042). Multivariate Cox regression analyses indicate that heart rate >110 (beats/min) (HR = 2.02; Cl 1.16–3.51; p = 0.013), inotropic support (HR = 3.25; Cl 1.20–8.82; p = 0.021), and hypopharygneal cancer (HR = 2.22; Cl 1.21–4.06; p = 0.010) were all significant independent predictors of poorer overall survival. Conclusions: HNC bleeding commonly represents the advanced disease stage. Recognition of associated factors aids in the risk stratification of patients with HNC bleeding.

Objective The mainstay of first-line treatment of parotid tumors is adequate surgical removal. The present study was conducted to compare the differences between parotidectomy with postauricular incision (PI) and modified Blair incision (MBI). Data Sources A systematic search of PubMed, Embase and the Cochrane Library was performed. Methods The data of interest and study characteristics were extracted from the included studies. Statistical analysis was performed with Comprehensive Meta-Analysis software (version 3; BioStat, Englewood, NJ). Dichotomous data and continuous data were analyzed by calculating the risk difference and the mean difference with the 95% confidence interval respectively. Results Four retrospective studies were included in the present meta-analysis. The pooled results revealed that the cosmetic satisfaction score was higher in the PI group (MD = 2.67; 95% CI, 2.12 to 3.23) and that intraoperative blood loss was lower in the PI group (MD = −55.35; 95% CI, −100.33 to −10.36). The operative duration (MD = −5.15; 95% CI, −24.06 to 13.75), tumor size (MD = −.07; 95% CI, −.27 to .13) and incidences of common postoperative complications were comparable between the two groups. Conclusions According to these findings, the use of PI in parotidectomies may be one of the options for improving cosmetic outcomes. This technique may be considered if oncological safety can be secured.