Regulation of HIF1a signaling in ER positive breast cancer by the E3 ubiquitin ligase RBCK1

RanBP2 type and C3HC4 type zinc finger containing protein 1 (RBCK1,) is a 58 kDa protein containing N-terminal ubiquitin like (UBL) domain, npl4 type zinc finger (NZF) domain and catalytic carbon terminal RBR domain. It is known that it has abnormal expression in tumors, making it a valuable diagnostic marker and drug target. A large number of studies have confirmed that in ER positive breast cancer, about 25%-40% of the tumor showed a visible hypoxia area. Under hypoxia, tumor cells can activate HIF1 pathway and widely activate the expression of downstream genes. Hypoxia inducible factor HIF-1 is composed of HIF-1a and HIF-1ß Two subunits, The protein level of HIF-1a is precisely regulated by oxygen concentration. Here, we report RBCK1, a RING family ubiquitin ligase that regulates HIF1a, promoting ER positive breast cancer growth and inhibiting apoptosis. Deletion of RBCK1 inhibits ER positive breast cancer growth and promotes cell death. RNA sequencing analysis showed that in ER positive breast cancer, RBCK1 may be an important modifier of HIF1a signal pathway. Further experiments showed that RBCK1 and HIF1a Interacts and inhibits HIF1a polyubiquitination to inhibit HIF1a degradation in ER positive breast cancer cells. These finding reveals a novel direct HIF1a regulator and a potential therapeutic target for ER positive breast cancer. Overall design: ER positive breast cancer cell mRNA samples were summarized in six samples, divided into two groups, siControl and siRBCK1