Cracking carboplatin resistance: Forward genetics identifies Hn1l/Jpt2 as a novel player in ovarian cancer’s escape from platinum therapy
Compuscript LtdPeer-Reviewed Publication
Ovarian cancer (OC) remains the deadliest gynecologic malignancy, with platinum-based chemotherapies such as carboplatin serving as the standard first-line treatment. However, the emergence of carboplatin resistance presents a major therapeutic challenge, and the underlying mechanisms remain incompletely understood. In this study, Dr. Tao Lu’s group from Indiana University School of Medicine, employed a novel validation-based insertional mutagenesis (VBIM) technique to identify genes that confer resistance to carboplatin in human epithelial OC cells. This screen revealed hematological and neurological expressed 1-like (HN1L/JPT2) as a previously unrecognized contributor to drug resistance. HN1L overexpression enhanced resistance to carboplatin, whereas shRNA-mediated knockdown sensitized OC cells to treatment. Mechanistically, HN1L promoted resistance by activating nuclear factor κB (NF-κB) signaling. In addition, HN1L depletion reduced anchorage-independent growth in vitro and impaired tumorigenicity in a xenograft model of OC. Immunohistochemical (IHC) analysis demonstrated elevated HN1L expression in both OC cell lines and patient tissues across multiple disease stages. These findings identify HN1L as a novel carboplatin resistance gene and suggest that targeting HN1L may represent a promising strategy for overcoming platinum resistance in OC.
- Journal
- Genes & Diseases
- Funder
- US National Institutes of Health, US National Institutes of Health, US National Institutes of Health, Kay Yow Cancer Fund (V Foundation for Cancer Research) (USA), Showalter Scholar fund from Indiana University School of Medicine (USA), University Melvin and Bren Simon Comprehensive Cancer Center (IUSCCC) fund (USA)