XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta

Posters
39.
EXPRESSION OF MICROPHTHALMIA-ASSOCIATED TraNSCRIPTION
faCTOR CRITICALLY REQUIRES ACTIVE SWI/SNF CHROMATIN
REMODELING COMPLEX
Ľubica Ondrušová and Jiří Vachtenheim
Laboratories of Molecular and Cell Biology, University Hospital Bulovka,
Prague 8, Czech Republic
Transcription factor MITF (microphthalmia-associated transcription factor) plays a central
role in the expression of melanocyte-specific genes, lineage determination, and survival
of embryonic, adult and malignant melanocytes. Here we show that the expression of
MITF requires the presence of active SWI/SNF chromatin remodeling complex, which
contains either Brg1 or Brm as a catalytic subunit. The SWI/SNF components were expressed
in melanoma cell lines and only one cell line with Brg1 loss was found (SK-MEL-5
cells). In several Brm/Brg1-expressing melanoma cell lines, knockdown of Brg1 severely
compromised MITF expression with a concomitant downregulation of MITF targets and
decreased cell proliferation. Although Brm was able to substitute for Brg1, sequential
knockdown of both Brm and Brg1 in 501mel resulted in loss of proliferation and viability.
Binding of Brg1 or Brm to the promoter of MITF was confirmed by chromatin immunoprecipitation.
Furthermore, microarray analysis revealed that osteopontin, IGF1 and
survivin, the proteins known to be associated with tumor progression, were reduced in
Brg1-depleted 501mel cells, suggesting that loss of SWI/SNF function negatively affects
survival pathways besides the MITF cascade. Our results demonstrate an essential role
of SWI/SNF for MITF expression in melanoma cells and suggest that a tissue-aimed inactivation
of the SWI/SNF complex might become an effective approach in the therapy
of melanoma.
XXII. Biochemistry Congress, Martin
157