Abstract:
Backgroud: Ovarian cancer is the most malignant gynecological tumor, although maintenance therapy with poly (ADP?ribose) polymerase inhibitor (PARPi) has improved patient outcomes, PARPi resistance remains a major challenge in clinical practice. Therefore, there is an urgent need to find new targets of PARPi resistance and to clarify the mechanisms of resistance.
Methods: 3 pairs of PARPi sensitive and PARPi resistance ovarian cancer tissues were selected to next generation sequencing. Differently expressed gene was used to taking the next steps in research. In terms of functional phenotype, proliferation, migration, invasion and apoptotic changes were observed in SKOV3 cell lines after knockdown and overexpression of UBE2A. Taking a survival analysis approach to clarify the relationship between UBE2A and poor survival prognosis in ovarian cancer Mechanistically, immunoprecipitation-mass spectrometry (IP-Mass) was used to find possibly proteins that can interact with UBE2A. The binding of these two proteins was then confirmed by the CO-IP method. RNA-seq and KEGG enrichment analyses were used to clarify the gene enrichment pathway after knockdown of UBE2A in the SKOV3 PARPi resistant cell lines.
Results: UBE2A was highly expressed in ovarian cancer PARPi resistant tissues and cells, and highly expression of UBE2A was associated with poor prognosis in ovarian cancer. Overexpression of UBE2A increased PARPi resistance and knockdown of UBE2A increased PARPi sensitivity in ovarian cancer. When UBE2A was inhibited, the therapeutic efficacy of PARPi was enhanced. UBE2A can interacted with WAC to activate the ATR/CHK1 axis.
Conclusion: Our study identified UBE2A as a newly target of PARPi resistance ovarian cancer, targeted UBE2A therapy may improve the treatment effective of PARPi. And we clarified the mechanism by which UBE2A interacted with WAC to activate the ATR/CHK1 axis to accumulated DNA damage leads to PARPi resistance in ovarian cancer.
Keywords: Ovarian cancer, PARPi resistance, UBE2A, WAC, DNA damage.
