Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis

Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes.AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although afew studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein weshow that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1)during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2.Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effectof metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering thetranscription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reducesH3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the antimetastasiseffect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higherphosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis viaPHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as thepotential epigenetic target in cancer metastasis.

Female Gender Was Associated With Increased Odds of Sleep Disturbance in Adult Chinese With Moderate-to-Severe Psoriasis:A Cross-Sectional Study

Objective:Up to 85.3%of patients with psoriasis experience sleep disturbance(SD).However,SD has not been characterized in Chinese patients with psoriasis,and the factors that affect SD among adult patients with psoriasis remain unclear.This study was performed to examine the risk of SD in patients with psoriasis compared with a control group of healthy individuals and to identify factors contributing to SD in patients with psoriasis.Methods:This was a cross-sectional,questionnaire-based,case-control study involving 142 adult participants with psoriasis and 142 healthy controls.The Pittsburgh Sleep Quality Index(PSQI)was administered to assess SD.Mild psoriasis was defined by Psoriasis Area and Severity Index and body surface area cut-offs of<10,and mild to severe psoriasis was determined by Psoriasis Area and Severity Index and body surface area cut-offs of≥10.Logistic regression was performed to investigate the associations.Results:The prevalence of SD(PSQI score of≥6)was 47.9%in adult patients with psoriasis.The mean PSQI score in patients with psoriasis was 6.1±3.7,which was higher than that in the control group(4.9±2.5,P<0.001).The risk of SD in the psoriasis group was 1.669 times higher(95%confidence interval,1.008-2.761;P=0.046)than that in the healthy group.Female sex(adjusted odds ratio,4.130;95%confidence interval,1.306-13.058;P=0.016)was significantly associated with an increased risk of SD in patients with moderate to severe psoriasis,whereas there were no significant factors affecting the risk of SD in patients with mild psoriasis.Conclusion:Patients with psoriasis were more likely than healthy controls to develop SD.In patients with moderate to severe psoriasis,but not in those with mild psoriasis,female sex was associated with a higher likelihood of SD.