TY - JOUR
T1 - Smoothened stabilizes and protects TRAF6 from degradation
T2 - A novel non-canonical role of smoothened with implications in lymphoma biology
AU - Qu, Changju
AU - Kunkalla, Kranthi
AU - Vaghefi, Amineh
AU - Frederiksen, John K.
AU - Liu, Yadong
AU - Chapman, Jennifer R.
AU - Blonska, Marzenna
AU - Bernal-Mizrachi, Leon
AU - Alderuccio, Juan Pablo
AU - Lossos, Izidore S.
AU - Landgraf, Ralf
AU - Vega, Francisco
N1 - Funding Information:
This work was supported by research funds from Sylvester Comprehensive Cancer Center/University of Miami (to FV), American Society of Hematology (ASH) Bridge Grant Program Award (to FV and RL) and National Natural Science Foundation of China (81400155), Jiangsu Natural Science Foundation of China (BK20140374), top-notch young health talents, 5th Suzhou health professionals program, 2018 (to CQ).
Funding Information:
This work was supported by research funds from Sylvester Comprehensive Cancer Center/University of Miami (to FV), American Society of Hematology (ASH) Bridge Grant Program Award (to FV and RL) and National Natural Science Foundation of China ( 81400155 ), Jiangsu Natural Science Foundation of China ( BK20140374 ), top-notch young health talents, 5th Suzhou health professionals program, 2018 (to CQ).
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Tumor necrosis factor receptor-associated factor 6 (TRAF6), an (K63) E3-ligase, plays a role in many biological processes and its activity is relevant in diffuse large B cell lymphoma (DLBCL) biology. Although molecules that trigger TRAF6 activation have been defined, those that stabilize TRAF6 and/or enhance TRAF6 function remain largely unclear. We found that TRAF6 amplifies pAKT signaling in DLBCL. Moreover, TRAF6 activation and stabilization of its ubiquitination profile are facilitated by smoothened (SMO), signal transducer of canonical Hedgehog signaling. Here, we report that SMO is needed to facilitate and maintain TRAF6-dependent elevated pAKT levels, and that the SMO/TRAF6 axis contributes to doxorubicin resistance in DLBCL. Mechanistically, we found that SMO, through its C-terminal tail, stabilizes and protects TRAF6 from degradation, an effect mediated by ubiquitin-specific protease-8. Moreover, this functional link between SMO and TRAF6 is reflected in DLBCL patients where high expression of both molecules correlates with poor prognosis. In summary, our study reveals a novel cell survival mechanism in which SMO stabilizes and protects TRAF6 from degradation. The axis SMO/TRAF6/AKT is highly relevant in the biology of DLBCL and is involved in doxorubicin resistance.
AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6), an (K63) E3-ligase, plays a role in many biological processes and its activity is relevant in diffuse large B cell lymphoma (DLBCL) biology. Although molecules that trigger TRAF6 activation have been defined, those that stabilize TRAF6 and/or enhance TRAF6 function remain largely unclear. We found that TRAF6 amplifies pAKT signaling in DLBCL. Moreover, TRAF6 activation and stabilization of its ubiquitination profile are facilitated by smoothened (SMO), signal transducer of canonical Hedgehog signaling. Here, we report that SMO is needed to facilitate and maintain TRAF6-dependent elevated pAKT levels, and that the SMO/TRAF6 axis contributes to doxorubicin resistance in DLBCL. Mechanistically, we found that SMO, through its C-terminal tail, stabilizes and protects TRAF6 from degradation, an effect mediated by ubiquitin-specific protease-8. Moreover, this functional link between SMO and TRAF6 is reflected in DLBCL patients where high expression of both molecules correlates with poor prognosis. In summary, our study reveals a novel cell survival mechanism in which SMO stabilizes and protects TRAF6 from degradation. The axis SMO/TRAF6/AKT is highly relevant in the biology of DLBCL and is involved in doxorubicin resistance.
KW - Diffuse large B cell lymphoma
KW - Hedgehog signaling pathway
KW - SMO
KW - TRAF6
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U2 - 10.1016/j.canlet.2018.08.020
DO - 10.1016/j.canlet.2018.08.020
M3 - Article
C2 - 30165192
AN - SCOPUS:85052787436
SN - 0304-3835
VL - 436
SP - 149
EP - 158
JO - Cancer Letters
JF - Cancer Letters
ER -