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

Abstract

The EGFR adaptor protein, CIN85, has been shown to promote breast cancer malignancy and hypoxiainducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill defined. Here we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase, PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SRC homology 3 domains of CIN85 interacted with the proline-arginine-rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9edited cells affected growth and migration properties, as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2 and uncovered an essential survival function in tumor cells by linking growth factor adaptors with hypoxia signaling. Significance: This study provides unprecedented evidence for an oxygen-independent mechanism of PHD2 regulation that has important implications in cancer cell survival.

PIK3R1 fusion drives chemoresistance in ovarian cancer by activating ERK1/2 and inducing rod and ring-like structures

“…CIN85 is a pro-oncogenic scaffold protein that can mediate various molecular mechanisms through its physical interaction with other proteins [48] . It is involved in multiple cancer cell-promoting functions [ 33 , 48 ], and its upregulation is associated with the advanced cancer stage and lymph node metastasis [33] [37][38]. CIN85 also activates RAS-MEK1/2-ERK1/2 signaling [33] , leading to enhanced cell adhesion, migration, and invasive behavior [34] , [35] , [36] .…”

HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?

“…The pro-oncogenic adaptor protein, CIN85 has been recently identified as an indirect regulator of PHD2 activity. Kozlova and colleagues have shown that disruption of the CIN85/PHD2 interaction using CRISPR/Cas9 editing not only led to lower levels of HIF-1α and HIF-2α, but also to significantly impaired tumor growth and migration in a breast carcinoma model (MDA-MB-231) [34]. The group of Vidimar explored the redox properties of a ruthenium organometallic compound (RDC11) that directly interacts with PHD2 and showed that RDC11 reduced HIF-1α protein level and function by promoting the enzymatic activity of PHD2.…”

Hypoxia in Cancer and Fibrosis: Part of the Problem and Part of the Solution

“…Otherwise, mTOR and the unfolding protein response (UPR) contribute to hypoxia tolerance [ 73 , 74 , 75 ]. In this chronic exposure, the participation of hypoxia in tumorigenesis is significant; for example, in patients with non-small-cell lung cancer, recurrent mutations of the epidermal growth factor receptor (EGFR) have been associated with hypoxia [ 76 , 77 ]. Thus, hypoxia pathway overactivation corresponds to an activation of alternative redundant pathways involved in cell survival [ 3 , 78 ].…”