Deregulation of E3
ubiquitin ligases is intimately implicated in
breast cancer pathogenesis and progression, but the underlying mechanisms still remain elusive. Here we report that RING finger
protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3
ubiquitin ligases, functions as a
tumor suppressor in
breast cancer. RNF144A was downregulated in a subset of primary
breast tumors and restoration of RNF144A suppressed
breast cancer cell proliferation, colony formation, migration, invasion in vitro,
tumor growth, and lung
metastasis in vivo. In contrast, knockdown of RNF144A promoted malignant phenotypes of
breast cancer cells. Quantitative proteomics and biochemical analysis revealed that RNF144A interacted with and targeted
heat-shock protein family A member 2 (HSPA2), a putative
oncoprotein that is frequently upregulated in human
cancer and promotes
tumor growth and progression, for ubiquitination and degradation. Notably, the
ligase activity-defective mutants of RNF144A impaired its ability to induce ubiquitination and degradation of HSPA2, and to suppress
breast cancer cell proliferation, migration, and invasion as compared with its wild-type counterpart. Moreover, RNF144A-mediated suppression of
breast cancer cell proliferation, migration, and invasion was rescued by ectopic HSPA2 expression. Clinically, low RNF144A and high HSPA2 expression in
breast cancer patients was correlated with aggressive clinicopathological characteristics and decreased overall and disease-free survival. Collectively, these findings reveal a previously unappreciated role for RNF144A in suppression of
breast cancer growth and
metastasis, and identify RNF144A as the first, to our knowledge,
E3 ubiquitin ligase for HSPA2 in human
cancer.