Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone

Abstract

Breast cancer metastasis suppressor 1 (BRMS1) is a member of the mSin3-HDAC transcription co-repressor complex. However, the proteins associated with BRMS1 have not been fully identified. Yeast two-hybrid screen, immuno-affinity chromatography, and co-immunoprecipitation experiments were performed to identify BRMS1 interacting proteins (BIPs). In addition to known core mSin3 transcriptional complex components RBBP1 and mSDS3, BRMS1 interacted with other proteins including three chaperones: DNAJB6 (MRJ), Hsp90, and Hsp70. Hsp90 is a known target of HDAC6 and reversible acetylation is one of the mechanisms that is implicated in regulation of Hsp90 chaperone complex activity. BRMS1 interacted with class II HDACs, HDAC 4, 5, and 6. We further found that BRMS1 is stabilized by Hsp90, and its turnover is proteasome dependent. The stability of BRMS1 protein may be important in maintaining the functional role of BRMS1 in metastasis suppression.

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

“…These studies however, did not involve microdissected tumor material that would ensure purity of the starting material in a heterogeneous tumor mass. Moreover, it has recently been shown that BRMS1 protein is stabilized by Hsp90 and that its turnover is proteosome-dependent [14]. Thus, assessment of BRMS1 mRNA may not be correlative to the protein levels of BRMS1.…”

“…BRMS1 has also been reported to suppress NFκ-B signaling through blockage of IκBα [11][12][13]. Further, BRMS1 gene regulatory mechanisms have been shown to involve histone deacetylases [14,15]. Proteomic as well as genomic analysis strategies have been used to reveal downstream targets of BRMS1 [16][17][18].…”

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

“…Some of these effects may be indirect and attributed to the activity of HDAC6 as a regulator of HSP90 chaperone functions Murphy et al, 2005;Hurst et al, 2006;Kong et al, 2006).…”

“…Accordingly, HDAC6 appears to play a role, directly or indirectly via HSP90, in the control of the stability of HIF-1a, a transcriptional regulator involved in tumor angiogenesis (Qian et al, 2006), the breast cancer metastasis suppressor 1, BRMS1 (Hurst et al, 2006), Bcr-Abl, FLT-3, c-Raf and AKT (Bali et al, 2005).…”

Neural stem cell self‐renewal requires the Mrj co‐chaperone

“…Bmi-1, a component of the Polycomb PRC1 complex that suppresses gene expression, is a critical regulator of stem cell self-renewal (Molofsky et al, 2003). Mrj, itself, has been implicated in transcriptional regulation (Dai et al, 2005;Hurst et al, 2006;Pan et al, 2008) and, at least in trophoblast cells, has a ''speckled'' nuclear expression pattern (Watson et al, 2007) reminiscent of Bmi-1 expression in other cell types (Stauffer et al, 2001). As a result, we hypothesized that Bmi-1 may be a substrate for Mrj.…”