RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect

Abstract

Hypoxia-inducible factors (HIFs) are master regulators of adaptive responses to low oxygen, and their α-subunits are rapidly degraded through the ubiquitination-dependent proteasomal pathway after hydroxylation. Aberrant accumulation or activation of HIFs is closely linked to many types of cancer. However, how hydroxylation of HIFα and its delivery to the ubiquitination machinery are regulated remains unclear. Here we show that Rho-related BTB domain-containing protein 3 (RHOBTB3) directly interacts with the hydroxylase PHD2 to promote HIFα hydroxylation. RHOBTB3 also directly interacts with the von Hippel-Lindau (VHL) protein, a component of the E3 ubiquitin ligase complex, facilitating ubiquitination of HIFα. Remarkably, RHOBTB3 dimerizes with LIMD1, and constructs a RHOBTB3/LIMD1-PHD2-VHL-HIFα complex to effect the maximal degradation of HIFα. Hypoxia reduces the RHOBTB3-centered complex formation, resulting in an accumulation of HIFα. Importantly, the expression level of RHOBTB3 is greatly reduced in human renal carcinomas, and RHOBTB3 deficiency significantly elevates the Warburg effect and accelerates xenograft growth. Our work thus reveals that RHOBTB3 serves as a scaffold to organize a multi-subunit complex that promotes the hydroxylation, ubiquitination and degradation of HIFα.

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

“…RHOBTB3, a Rho GTPase, promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppressing the Warburg effect [53]. Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect [27].…”

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

“…Furthermore, Rhobtb3 mRNA was identified by cDNA microarray as one of the most differentially down-regulated genes in ELL2 knockout mouse prostate in mice at 3 mos of age (see Table S1) as well as in the anterior prostates of mice at 18 mos of age (see Figure 5). RHOBTB3 was recently shown to promote the hydroxylation, ubiquitination and degradation of HIFα (Zhang, et al 2015). Increased expression of HIF1α has been reported as a potential early ‘angiogenic event’ in the development of prostate cancer in the TRAMP model (Huss et al 2001) and is negatively regulated by EAF2 (Chen et al 2014).…”

The Pro-Oncogenic Adaptor CIN85 Acts as an Inhibitory Binding Partner of Hypoxia-Inducible Factor Prolyl Hydroxylase 2

“…The association of PHD2 with these adaptors promotes the assembly of hydroxylation-dependent degradation machinery, which further contributes to lower levels of both HIF1a and HIF2a (42). Because decreased levels of HIFas are usually considered to favor patient survival, the participation of RUNX3 (43), ING4 (44), LIMD1 (45), and RHOBTB3 (46) in downregulating HIFas additionally confirms the known tumorsuppressing role of these proteins in human cancers. Interestingly, our data show that the strength of the interaction between PHD2 and CIN85 varies between the cell lines investigated.…”