Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression

Abstract

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin–proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.

NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5

“…as a consequence of hypoxiainduced ubiquitination and proteasomal degradation as previously shown for other tumor suppressor proteins, e.g. "deleted in breast cancer 1" (DBC1; Liu et al, 2022).…”

YTHDF1 enhances stemness and chemoresistance in triple‐negative breast cancer cells by upregulating SIAH2

“…SIAH2 mediates the ubiquitination and degradation of substrates, including key proteins of multiple signaling pathways 13 . Among them, the key protein LATS2 of the Hippo pathway was confirmed to interact with SIAH2 and be degraded by SIAH2 37 .…”

“…SIAH family proteins are analogs of Drosophila SINA proteins, which have E3 ubiquitin ligase activity and can mediate the degradation of various proteins through the ubiquitination pathway 29,30 . SIAH is divided into two subtypes, SIAH1 and SIAH2, 31 among which SIAH2 has the effect of promoting tumor cell growth, and can promote the development of ovarian cancer, breast cancer, gastric cancer, and other malignant tumors through various pathways 13,32–34 . In breast cancer, SIAH2 primarily shows tumorigenic functions.…”

“…29,30 SIAH is divided into two subtypes, SIAH1 and SIAH2, 31 among which SIAH2 has the effect of promoting tumor cell growth, and can promote the development of ovarian cancer, breast cancer, gastric cancer, and other malignant tumors through various pathways. 13,[32][33][34] In breast cancer, SIAH2 primarily shows tumorigenic functions. Studies have found that SIAH2 silencing reduced breast tumor growth in vivo.…”

“…Seven in absentia homology 2 (SIAH2) is a subtype of the SIAH family protein, and studies have confirmed that SIAH2 promotes tumor progression through multiple pathways. 13,14 Meanwhile, the inhibition of SIAH2 improves the chemosensitivity of tumor cells. 14 Large tumor suppressor 1/2 (LATS1/2) is a key component of the Hippo pathway.…”