SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors.
The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.
Department of Medical Biotechnologies, University of Padua School of Medicine, Viale Colombo 3, 35131 Padua, Italy.
Marco
M
Montagner
Elena
E
Enzo
Mattia
M
Forcato
Francesca
F
Zanconato
Anna
A
Parenti
Elena
E
Rampazzo
Giuseppe
G
Basso
Genesio
G
Leo
Antonio
A
Rosato
Silvio
S
Bicciato
Michelangelo
M
Cordenonsi
Stefano
S
Piccolo
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D056767:Cyclin G2 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis
D051792:Basic Helix-Loop-Helix Proteins; D056767:Cyclin G2; C422085:BHLHE41 protein, human; C101593:CCNG2 protein, human