Yueyin Pan

The first Tudor domain (Tudor1) of PHF20L1 recognizes (non)histone methylation to play versatile roles. However, the underlying ligand-recognition mechanism remains unknown as a closed state revealed in the free-form structure. NMR relaxation dispersion and molecular dynamics simulations suggest a pre-existing low-population conformation with a remarkable rearrangement of aromatic cage residues of PHF20L1 Tudor1. Such an open-form conformation is utilized to recognize lysine 142 methylated DNMT1, a cosolvent, and an NMR fragment screening hit, respectively, as revealed by the complex crystal structures. Intriguingly, the ligand binding capacity was enhanced by mutation that tunes up the open-state population only. The recognition of DNMT1 by PHF20L1 was further validated in cancer cells. This conformational selection mechanism shall entitle the discovery of small molecule inhibitors against the seemingly “undruggable” PHF20L1 Tudor1.

The first Tudor domain of PHF20L1 (PHF20L1 Tudor1) recognizes both histone methylation and non-histone methylation to play versatile roles, e.g., PHF20L1 Tudor1 binds to the oncogenic target DNA (cytosine-5) methyltransferase 1 (DNMT1) to prevent it from degradation. However, the crystal structure of the PHF20 Tudor domain, a homolog of PHF20L1, reveals a closed aromatic cage of the Tudor domain. It is thus highly desirable to interrogate the ligand-recognition mechanism of PHF20L1 Tudor1, which will in turn validate the potential druggability of this target. Here, we solved the crystal structure of the free form PHF20L1 Tudor1, which adopts the closed conformation similar to PHF20. NMR relaxation dispersion and molecular dynamics (MD) simulations suggest a pre-existing low-population conformation with a remarkable rearrangement of aromatic cage residues. Such structural rearrangement is further revealed by the crystal structures of PHF20L1 Tudor1 in complex with the lysine 142 methylated (K142 ^me1 ) DNMT1, and a small molecule cosolvent 2-(N-morpholino)ethanesulfonic acid (MES), respectively. This result thus ignites interest in the discovery of small molecule inhibitors against PHF20L1 Tudor1. The hit identified from NMR fragment-based screening protrudes into the same open form aromatic cage of PHF20L1 Tudor1, and blocks the interaction between PHF20L1 Tudor1 and methylated DNMT1. Further free form crystal structures of key mutants reveal one open form and one closed form aromatic cage, which is energetically trapped observed in the NMR relaxation dispersion and MD simulations. The binding of DNMT1 with PHF20L1 Tudor1 mutants was also recapitulated in cancer cells. The mutagenesis thus alters the structure, dynamics and eventually the function of PHF20L1 Tudor1. Our results demonstrate that PHF20L1 Tudor1 utilizes the same conformational selection mechanism to recognize ligands, regardless of whether it is a natural substrate or a small molecule identified from fragment-based screening. Albeit at a low population, the pre-existing ligand-binding conformation shall shift the paradigm in the druggability assessment of a dynamic protein, even though it may lack a small molecule binding pocket in its free form structure. The inhibition of PHF20L1 paves an alternative way to target DNMT1 degradation.

Purpose: Previous studies investigating the association between interleukin-17A (IL-17A) G197A polymorphism and gastric cancer risk have provided inconsistent results. We, therefore, conducted this meta-analysis to clarify the association between IL-17A G197A polymorphism and gastric cancer risk. Methods: We searched PubMed, Excerpta Medica Database, and CNKI databases to identify relevant studies up to June 10, 2017. A total of 16 case-control studies including 6,624 cases and 7,631 controls were identified. Results: Overall, significant associations between IL-17A G197A polymorphism and gastric cancer risk were observed (A vs G: OR =1.24, 95% CI =1.14–1.36; AA vs GG: OR =1.63, 95% CI =1.35–1.96; GA vs GG: OR =1.12, 95% CI =1.01–1.25; AA+GA vs GG: OR =1.23, 95% CI =1.11–1.35; AA vs GA+GG: OR =1.54, 95% CI =1.27–1.87). Similar associations were also observed in Asian population (A vs G: OR =1.25, 95% CI =1.15–1.37; AA vs GG: OR =1.62, 95% CI =1.33–1.97; GA vs GG: OR =1.16, 95% CI =1.07–1.25; AA+GA vs GG: OR =1.24, 95% CI =1.15–1.33; AA vs GA+GG: OR =1.51, 95% CI =1.23–1.85), in Caucasian population (AA vs GA+GG: OR =2.19, 95% CI =1.40–3.44), and in the hospital-based controls’ subgroup (A vs G: OR =1.30, 95% CI =1.17–1.45; AA vs GG: OR =1.81, 95% CI =1.46–2.25; AA+GA vs GG: OR =1.27, 95% CI =1.12–1.43; AA vs GA+GG: OR =1.71, 95% CI =1.34–2.18). Conclusions: The current meta-analysis suggests that IL-17A G197A polymorphism might enhance gastric cancer risk.

The prognostic value of lysine-specific demethylase 1 (LSD1) overexpression in various cancers has been investigated by many studies with inconsistent results. A meta-analysis was performed to assess the association between LSD1 and overall survival (OS) in cancer patients. Eligible studies were identified by searching the online databases PubMed and China National Knowledge Infrastructure up to February 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between LSD1 expression and prognosis of different cancers. In total, nine studies with 1,149 cancer patients were included for final analysis. The meta-analysis suggested that LSD1 overexpression was associated with poor OS in cancer patients (HR =1.80, 95% CI: 1.39–2.34, P=0.000). Subgroup analysis by ethnicity, cancer type and HR estimate also showed that high levels of LSD1 were significantly correlated with OS. The meta-analysis showed that LSD1 overexpression may be associated with a worse prognosis in cancer patients.

Despite the use of modern immunochemotherapy regimens, a significant proportion of diffuse large B-cell lymphoma (DLBCL) patients will relapse. We proposed absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) as a new prognostic factor in relapsed or primary refractory DLBCL.

FAS/FASL gene promoter polymorphisms are associated with cervical cancer risk, however, results from previous studies have been conflicting. To obtain a more precise estimation of the association between these polymorphisms and cancer risk, a meta-analysis was performed. All eligible studies up to November 1st, 2012, concerning FAS-670 A/G, FAS-1377 G/A and FASL-844 T/C polymorphisms and cervical cancer risk, were collected from the following electronic databases: PubMed, Excerpta Medica Database and Chinese Biomedical Literature Database. The odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the strength of the association via the additive, codominant, dominant and recessive models. In total, 10 publications with 11 case-control studies (10 on FAS-670 A/G, 5 on FAS-1377 G/A and 6 on FASL-844 T/C polymorphisms) were included in this meta-analysis. No association between FAS-670 A/G, FAS-1377 G/A and FASL-844 T/C polymorphisms and cervical cancer susceptibility for all the genetic models was identified. Following stratification of the studies by ethnicity or source of controls, similar results were obtained. In conclusion, our findings showed that the FAS-670 A/G, FAS-1377 G/A and FASL-844 T/C polymorphisms are not associated with cervical cancer risk. Future studies with larger sample sizes are required to further evaluate these associations.

Lack of Association Between Interleukin-8-251 T>A Polymorphism and Colorectal Cancer Risk: a Meta-analysis based on 3,019 Cases and 3,984 Controls Colorectal cancer;polymorphism;meta-analysis;interleukin-8; Purpose: The results of recent published studies focusing on IL-8 polymorphism in colorectal cancer susceptibility have often been inconsistent. We therefore carried out a meta-analysis based on independent studies to assess the association. Methods: Nine case-control studies with 7,003 individuals (3,019 cases and 3,984 controls) were included in this meta-analysis through searching the databases of PubMed, Excerpta Medica Database (EMBASE), and Chinese Biomedical Literature Database (CBM; Chinese) (up to Aug 1st, 2012). The odds ratio (OR) and 95% confidence interval (95%CI) were used to assess the strength of the association. Meta-analysis was conducted in a fixed/random effect model. Results: No obvious associations were found for all genetic models when all studies were pooled into the meta-analysis (for A vs. T: OR = 1.084, 95% CI = 0.971-1.209, P = 0.019; for TA vs. TT: OR = 1.18, 95% CI = 0.943-1.475, P = 0.001; for AA vs. TT: OR = 1.155, 95% CI = 0.916-1.456, P = 0.014; for AA+TA vs. TT: OR = 1.170, 95% CI =0.953-1.437, P = 0.001; for AA vs. TT+TA: OR = 1.044, 95% CI = 0.886-1.230, P = 0.097). In the subgroup analyses by ethnicity (Caucasian) and source of controls (population based), also no significant associations were found for all genetic models. Conclusions: Result suggests that the IL-8-251T>A polymorphism is not associated with colorectal cancer risk. Because of the limitations of this meta-analysis, this finding demands further investigation.