Editors' ChoiceCancer

This SCAI Limits Invasion

Science Signaling  05 May 2009:
Vol. 2, Issue 69, pp. ec153
DOI: 10.1126/scisignal.269ec153

Growth factors stimulate the transcription of a subset of serum response factor (SRF) target genes through a pathway involving the small guanosine triphosphatase RhoA and its effector Diaphanous 1 (Dia1). RhoA activation leads to a decrease in the abundance of G-actin, freeing the actin-binding transcriptional coactivator MAL (megakaryocytic acute leukemia) to associate with SRF (see Juliano). Brandt et al. identified a previously uncharacterized protein, which they called SCAI (suppressor of cancer cell invasion), in a screen for proteins that interact with Dia1 and determined that it contained a nuclear localization signal. Identified in mouse, SCAI was conserved from flies to humans, was expressed in most tissues tested, and was enriched in the nucleus. Although SCAI overexpression in HEK293 cells had no effect on basal activity of an SRF reporter, it inhibited serum-dependent SRF activation. SCAI also inhibited SRF activation by constitutively active RhoA or Dia1 mutants, an F-actin–stabilizing form of β-actin, or overexpressed MAL, but failed to inhibit constitutively active SRF. SCAI coimmunoprecipitated with MAL and SRF from nuclear fractions of HEK293 cells, and, in 3T3 cells, SCAI knockdown increased basal SRF reporter activity. Intriguingly, SCAI depletion promoted the invasive migration into Matrigel of cells from human cancer cell lines, whereas SCAI overexpression inhibited it. SCAI mRNA abundance was decreased in several human tumors and was inversely correlated with the invasiveness of cancer cell lines. Microarray analysis of a breast cancer line revealed that SCAI depletion by siRNA increased the expression of the gene encoding β1-integrin (ITGB1), an effect confirmed in various cell lines; moreover, a β1-integrin–blocking antibody inhibited SCAI-siRNA–dependent invasion. A complex consisting of SCAI, MAL, and SRF formed at a putative SRF consensus sequence (CArG box) on the human β1-integrin gene; SCAI recruitment to this complex depended on regions through which it bound MAL. Furthermore, SCAI inhibited transcriptional activation of a reporter that contained a region of the β1-integrin gene with the CArG box by constitutively active forms of RhoA, Dia1, and MAL. The authors thus conclude that SCAI participates in the RhoA-Dia1-MAL-SRF pathway to regulate β1-integrin signaling and thereby cancer cell invasion.

D. T. Brandt, C. Baarlink, T. M. Kitzing, E. Kremmer, J. Ivaska, P. Nollau, R. Grosse, SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of β1-integrin. Nat. Cell Biol. 11, 557–568 (2009). [PubMed]

R. Juliano, SCAI blocks MAL-evolent effects on cancer cell invasion. Nat. Cell Biol. 11, 540–542 (2009). [PubMed]