Open Access

Tabea L. Fullstone, Helene Rohm, Till Kaltofen, Sophia Hierlmayer, Juliane Reichenbach, Simon Schweikert, Franziska Knodel, Ann-Kathrin Loeffler, Doris Mayr, Udo Jeschke, Sven Mahner, Mirjana Kessler, Fabian Trillsch, Philipp Rathert

• Platinum-based combination chemotherapy remains the backbone of first-line treatment for patients with advanced epithelial ovarian cancer (EOC). While most patients initially respond well to the treatment, patients with relapse ultimately develop platinum resistance. This study identified FLYWCH-type zinc finger-containing protein 1 (FLYWCH1) as an important regulator in the resistance development process. We showed that the loss of FLYWCH1 promotes platinum resistance in EOC cells, and the low FLYWCH1 expression is correlated with poor prognosis of EOC patients. In platinum-sensitive cells, FLYWCH1 colocalizes with H3K9me3, but this association is significantly reduced when cells acquire resistance. The suppression of FLYWCH1 induces gene expression changes resulting in the deregulation of pathways associated with resistance. In line with its connection to H3K9me3, FLYWCH1 induces gene silencing in a synthetic reporter assay and the suppression of FLYWCH1 alters H3K9me3 at promoterPlatinum-based combination chemotherapy remains the backbone of first-line treatment for patients with advanced epithelial ovarian cancer (EOC). While most patients initially respond well to the treatment, patients with relapse ultimately develop platinum resistance. This study identified FLYWCH-type zinc finger-containing protein 1 (FLYWCH1) as an important regulator in the resistance development process. We showed that the loss of FLYWCH1 promotes platinum resistance in EOC cells, and the low FLYWCH1 expression is correlated with poor prognosis of EOC patients. In platinum-sensitive cells, FLYWCH1 colocalizes with H3K9me3, but this association is significantly reduced when cells acquire resistance. The suppression of FLYWCH1 induces gene expression changes resulting in the deregulation of pathways associated with resistance. In line with its connection to H3K9me3, FLYWCH1 induces gene silencing in a synthetic reporter assay and the suppression of FLYWCH1 alters H3K9me3 at promoter regions and repeat elements. The loss of FLYWCH1 leads to the derepression of LTR and Alu repeats, thereby increasing transcriptional plasticity and driving the resistance development process. Our data highlight the importance of FLYWCH1 in chromatin biology and acquisition of platinum resistance through transcriptional plasticity and propose FLYWCH1 as a potential biomarker for predicting treatment responses in EOC patients.…