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

So Hee Kwon,Sang Ah Yi,Jung Yoo,Go Woon Kim,Jeung-Whan Han

doi:10.3390/ijms21175976

Abstract

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.

Highlights

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth common cause of mortality in women worldwide, with an estimated 570,000 cases and 311,000 deaths in 2018, despite the advancement of Papanicolaou smear screening and prophylactic vaccines [1]
Our results suggest that the inhibition of nuclear export of HP1γ facilitates overcoming the cisplatin resistance caused by human papillomavirus (HPV)-mediated loss of p53 in cervical cancer cells
As our previous study showed that overexpression of HP1γ induces apoptosis in cervical cancer cells by inhibiting the UBE2L3-mediated p53 degradation [15], we examined the involvement of HP1γ-UBE2L3-p53 axis in sensitizing cervical cancer cells to cisplatin

Summary

Introduction

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth common cause of mortality in women worldwide, with an estimated 570,000 cases and 311,000 deaths in 2018, despite the advancement of Papanicolaou smear screening and prophylactic vaccines [1]. In the early-stage of cervical cancer, surgery represents the primary treatment possibly associated with radiotherapy. In the advanced stages, radiochemotherapy or chemotherapy alone are the most appropriate choice treatment options are very limited for recurred cervical cancer. The patients with advanced or recurrent cervical cancer have poor prognosis, with chemotherapy response rates ranging between 20% and 36% and a 1-year survival rate between only 10% and 20%. Patients with persistent, recurrent, or metastatic cervical cancer not amenable with surgery or radiotherapy are treated in combination with paclitaxel and either cisplatin or topotecan [4]. The combination treatment of those chemotherapy and bevacizumab, anti-angiogenesis drug, improves overall survival of advanced cervical cancer patients. The molecular mechanism underlying cisplatin-induced anticancer effects involves DNA damage response and apoptosis induction by causing DNA lesions [5]. When cisplatin-induced DNA damage exceeds the DNA repair capacity, cisplatin exerts anticancer effects by inducing apoptosis [5]

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Conclusion