Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway.
Defining the precise molecular strategies that coordinate patterns of transcriptional responses to specific signals is central for understanding normal development and homeostasis as well as the pathogenesis of hormone-dependent cancers. Here we report specific prostate cancer cell/macrophage interactions that mediate a switch in function of selective androgen receptor antagonists/modulators (SARMs) from repression to activation in vivo. This is based on an evolutionarily conserved receptor N-terminal L/HX7LL motif, selectively present in sex steroid receptors, that causes recruitment of TAB2 as a component of an N-CoR corepressor complex. TAB2 acts as a sensor for inflammatory signals by serving as a molecular beacon for recruitment of MEKK1, which in turn mediates dismissal of the N-CoR/HDAC complex and permits derepression of androgen and estrogen receptor target genes. Surprisingly, this conserved sensor strategy may have arisen to mediate reversal of sex steroid-dependent repression of a limited cohort of target genes in response to inflammatory signals, linking inflammatory and nuclear receptor ligand responses to essential reproductive functions.
Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Ping
P
Zhu
Sung Hee
SH
Baek
Eliot M
EM
Bourk
Kenneth A
KA
Ohgi
Ivan
I
Garcia-Bassets
Hideki
H
Sanjo
Shizuo
S
Akira
Paul F
PF
Kotol
Christopher K
CK
Glass
Michael G
MG
Rosenfeld
David W
DW
Rose
D000595:Amino Acid Sequence; D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002450:Cell Communication; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D000726:Androgen Antagonists; D007375:Interleukin-1; D011987:Receptors, Steroid