ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE

Abstract:

Ovarian cancer is a complex disease associated with multiple genetic and epigenetic alterations. The emergence of treatment resistance in most patients causes ovarian cancer to become incurable, and novel therapies remain necessary. We identified epigenetic regulator ATPase family AAA domain-containing 2 (ATAD2) is overexpressed in ovarian cancer and is associated with increased incidences of metastasis and recurrence. Genetic knockdown of ATAD2 or its pharmacological inhibition via ATAD2 inhibitor BAY-850 suppressed ovarian cancer growth and metastasis in both in vitro and in vivo models. Transcriptome-wide mRNA expression profiling of ovarian cancer cells treated with BAY-850 revealed that ATAD2 inhibition predominantly alters the expression of centromere regulatory genes, particularly centromere protein E (CENPE). In ovarian cancer cells, changes in CENPE expression following ATAD2 inhibition resulted in cell-cycle arrest and apoptosis induction, which led to the suppression of ovarian cancer growth. Pharmacological CENPE inhibition phenotypically recapitulated the cellular changes induced by ATAD2 inhibition, and combined pharmacological inhibition of both ATAD2 and CENPE inhibited ovarian cancer cell growth more potently than inhibition of either alone. Thus, our study identified ATAD2 as regulators of ovarian cancer growth and metastasis that can be targeted either alone or in combination with CENPE inhibitors for effective ovarian cancer therapy.

Audience Take Away Notes:

• Ovarian cancer remains a challenge for modern oncology practice because of its late stage detection, poor survival when the disease is metastasized, and lack of effective therapies. Identification and targeting of ATAD2 can be employed as a new therapeutic intervention for ovarian cancer
• New epigenetic regulator is involved in ovarian cancer growth and progression
• Clinically relevant targetable mechanism for ovarian cancer therapy

Biography:

Dr. Gupta did her PhD at Max Planck Institute for Molecular Genetics, Berlin, Germany, studying protein translation, leading to the discovery of 70S-scanning initiation. She then worked at Yale University, focusing on cancer therapeutics, resulting in publications in journals like Cancer Discovery, Cell Reports Medicine, PNAS, Cell Reports etc. Currently, she is Associate Professor and Associate scientist at O'Neal Comprehensive Cancer Center at UAB. Her lab focuses on identifying new molecules and pathways and studying their role in tumor initiation and progression. Her long-term goal is to develop novel, more effective and durable cancer therapies.