SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors (Nature, 2012, 487:380-384)

報告日期: 2012/10/12
報告時間: 17:10/18:00
報告學生: 李祐華 (英文報告)
講評老師: 陳炳焜
附件下載: 下載[1231-1348725213-1.pdf] 

 

SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors

 

Nature 487, 380-384 (2012)

 

Speaker: Yo-Hua Li                             Date: 2012/10/12 16:10-17:00

Commentator: Dr. Ben-Kuen Chen                           Place: Room 602

 

Breast cancer is the most common incident form of cancer in women. Thanks to well classification in the clinical management according to the expression of steroid hormone receptors (estrogen and progesterone receptors) and ERRB2 (also known as HER2), the effective therapies have been developed for patients with hormone-receptor positive or HER2-positive breast cancers. In contrast, breast cancer with the lack of expression of above receptors, defined as triple-negative breast cancer (TNBC), has more aggressive phenotypes, especially in invasion and metastasis, and always leads to poor prognosis. However, the molecular determinants of malignant breast cancer remain only partially understood. Recent studies reported that TAp63, as a crucial tumor suppressor, could inhibit invasive and metastatic behaviors in vitro, and genetically ablated in mice developed spontaneous aggressive carcinomas [1]. Here, the author showed that the lower expression of p63-regulated SHARP1 (also known as BHLHE41 or DEC2) was correlated to higher probability of developing metastasis and lower survival rate in TNBC-patients. Gene set enrichment analysis revealed that this signature of low SHARP1 was strongly associated with high hypoxia inducible factor (HIF) activity. Because SHARP1 physically interacted with HIF1a in trasfected-COS7 cells [2], the author wanted to determine whether SHARP1 controls HIFs activity by overexpressing SHARP1 in MDA-231 (metastatic TNBC cell line) or silencing endogenous SHARP1 in MII (non-metastatic TNBC cell line). Results showed that SHARP1 was essential and sufficient for limiting HIF downstream target genes expression. Moreover, overexpression of SHARP1 in MDA-231 dramatically suppressed cell migration, invasion, and metastasis by inhibiting HIFs. Furthermore, the author demonstrated that SHARP1 promoted HIF1a degradation by increasing the interaction with 20s proteasome, and this phenomenon was independent of oxygen levels and pVHL. In summary, SHARP1 controls intrinsic stability of HIF proteins and then inhibits cell metastasis and invasion in TNBC. This work sheds light on how TNBC acquires invasiveness and metastatic properties, and low expression of SHARP1 might be an indicator of malignant tumors in breast cancer.

 

References:

1.         Su, X., et al., TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 467(7318): p. 986-90.

2.         Sato, F., et al., Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression. Genes Cells, 2008. 13(2): p. 131-44.