TY - JOUR
T1 - SMARCB1 regulates the hypoxic stress response in sickle cell trait
AU - Soeung, Melinda
AU - Perelli, Luigi
AU - Chen, Ziheng
AU - Dondossola, Eleonora
AU - Ho, I. Lin
AU - Carbone, Federica
AU - Zhang, Li
AU - Khan, Hania
AU - Le, Courtney N.
AU - Zhu, Cihui
AU - Peoples, Michael D.
AU - Feng, Ningping
AU - Jiang, Shan
AU - Zacharias, Niki Millward
AU - Minelli, Rosalba
AU - Shapiro, Daniel D.
AU - Deem, Angela K.
AU - Gao, Sisi
AU - Cheng, Emily H.
AU - Lucchetti, Donatella
AU - Walker, Cheryl L.
AU - Carugo, Alessandro
AU - Giuliani, Virginia
AU - Heffernan, Timothy P.
AU - Viale, Andrea
AU - Tannir, Nizar M.
AU - Draetta, Giulio F.
AU - Msaouel, Pavlos
AU - Genovese, Giannicola
N1 - Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
PY - 2023/5/23
Y1 - 2023/5/23
N2 - Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.
AB - Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.
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U2 - 10.1073/pnas.2209639120
DO - 10.1073/pnas.2209639120
M3 - Article
C2 - 37186844
AN - SCOPUS:85159464859
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
M1 - e2209639120
ER -