2021 Mentored Investigator Grant Recipient — Wei Zhou, PhD
Wei Zhou, PhD
The Wistar Institute
Targeting the mevalonate pathway in ARID1A-mutated ovarian cancer
Project Summary
Epithelial ovarian cancer (EOC) is a major cause of death among women worldwide. Ovarian clear cell carcinoma (OCCC) is a relatively rare histological subtype of EOC that is characterized by chemoresistance and poor prognosis when diagnosed at advanced stages. OCCCs are characterized by a distinct set of genetic features. Notably, ARID1A is mutated in more than 50% of OCCCs. ARID1A is a tumor suppressor gene and ARID1A mutation is identified as a genetic driver of OCCCs. ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, targets the complex to different genes to regulate their transcription. Loss of ARID1A correlates with late-stage disease and predicts early recurrence of OCCCs. Therapeutic strategies harnessing ARID1A mutation in ovarian cancers remain to be fully explored. The overall goal of this proposal is to develop a novel therapeutic approach to target ARID1A-mutated ovarian cancers. ARID1A is the DNA binding subunit of the SWI/SNF chromatin-remodeling complex. The SWI/SNF chromatin-remodeling complex plays a crucial role in the epigenetic regulation of chromatin accessibility and gene transcription. Loss of ARID1A cannot be directly targeted. My preliminary data shows that the loss of ARID1A leads to the downregulation of enzymes in the mevalonate pathway. The mevalonate pathway plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, non-sterol isoprenoids and ubiquinone. Genome-wide ARID1A distribution profile by ChIP-seq analysis shows that Sterol Regulatory Element Binding Transcription Factor 2 (SREBF2), the master regulator of the mevalonate pathway, is a direct ARID1A target gene, indicated that ARID1A regulates the mevalonate pathway via controlling the transcription of SREBF2. The mevalonate pathway is involved in the regulation of cell survival, proliferation, and energy homeostasis. Hence, ARID1A-mutation might confer sensitivity to the inhibition of the mevalonate pathway by exacerbating sterol isoprenoids shortage induced by ARID1A loss. Statins, also known as HMG-CoA reductase inhibitors, are a class of cholesterol-lowering drugs that inhibit the mevalonate pathway by targeting HMGCR, the rate-limiting enzyme of the pathway. Intriguingly, my preliminary data shows that ARID1A deficient cells are hypersensitive to clinically applicable HMGCR inhibitors such as Simvastatin. Thus, my central hypothesis is that ARID1A-mutated OCCC can be therapeutically targeted by inhibiting the mevalonate pathway through repurposing clinically safe inhibitors of the mevalonate pathway. This proposal aims to elucidate the molecular mechanism underlying the observed sensitivity to the inhibition of the mevalonate pathway and develop a novel therapeutic approach for ARID1A-mutated ovarian cancers, which accounts for ~50% of OCCC. Since clinically applicable mevalonate pathway inhibitors such as statins are readily available and safe, the newly developed therapeutic strategy will have an immediate impact on ARID1A-mutated ovarian cancer patients.