So Hee Kwon

Ubiquitin-mediated stabilization of KDM5B drives chemoresistance via repression of dual-specificity phosphatase 4 in ovarian cancer

Despite advances in therapeutic regimens for managing cancer progression, ovarian cancer (OVC) still depends on platinum-based chemotherapy as its first-line treatment. Acquired resistance is accompanied by abnormal alterations in epigenetic regulation; however, in-depth mechanistic studies on cisplatin-resistant OVC are lacking. Herein, we show that abnormal overexpression of histone lysine demethylase 5B (KDM5B), but not KDM5A, strongly correlates with cisplatin resistance and OVC tumor progression. Genome-wide sequencing data revealed that KDM5B removes H3K4me3 from the promoter of dual-specificity phosphatase 4 (DUSP4), activating the MAPK pathway to increase cisplatin resistance. We also found that KDM5B protein stability is dynamically controlled via the ubiquitin-proteasome system (UPS), which is mediated by ubiquitin-specific protease 7 (USP7), F-box and WD repeat domain-containing 7 (FBXW7), and homeodomain-interacting protein kinase 1 (HIPK1). KDM5B and USP7 depletion effectively resensitizes OVC to cisplatin resistance, whereas DUSP4 silencing results in resistance in vitro and in vivo. Targeting KDM5B and USP7 synergistically represses tumor progression and increases sensitivity to cisplatin. Overall, we propose two new UPS-associated proteins, USP7 and FBXW7, which are responsible for abnormal KDM5B protein regulation, and suggest a novel mechanism to overcome cisplatin resistance in OVC by targeting the KDM5B-DUSP4 axis.

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance.