Olle Sangfelt's Group
Our research is focused on how protein ubiquitylation control cellular integrity and how alterations of components of the ubiquitin-machinery contribute to cancer development and progression.
Under normal growth conditions the activity of proteins is tightly regulated to ensure proper cellular homeostasis. Proteins undergo extensive post-translational modifications (PTMs) that control their stability and/or interaction with other proteins, as well as with RNA and DNA molecules. One specific type of PTM is the covalent attachment of the small protein ubiquitin (Ub), in a process known as ubiquitylation. Our research is focused on how deregulation of the ubiquitin-machinery contributes to cancer development and drug resistance.
Ubiquitylation is executed through an enzymatic multistep reaction involving E1-activating, E2-conjugating, and E3 ubiquitin ligases responsible for target substrate recognition. Importantly, protein ubiquitylation and proteasomal degradation is counteracted by deubiquitylating enzymes (DUBs), highlighting the reversibility of the system, analogous to that of kinase-phosphatase activities catalyzing protein phosphorylation-dephosphorylation reactions. A wealth of experimental evidence demonstrates that phosphorylation and ubiquitylation are interconnected processes which open up diverse opportunities to target the ubiquitin-system in cancer.
We postulate that specific SCF E3 ubiquitin ligases, through targeted degradation of oncogenic substrates, function as key regulators of several tumor-supportive cellular programs, potential predictive markers and targets for therapeutic intervention. The projects are focused on characterization of FBW7, FBXL12 and FBXO28, their regulatory functions during replication stress, checkpoint activation/recovery and identification of novel drugs targeting these SCF ubiquitin ligases.
FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress.
Brunner A, Li Q, Fisicaro S, Kourtesakis A, Viiliäinen J, Johansson HJ, Pandey V, Mayank AK, Lehtiö J, Wohlschlegel JA, Spruck C, Rantala JK, Orre LM, Sangfelt O
Mol Cell 2023 Aug;():
Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia.
Alena Malyukova, Mari Lahnalampi, Ton Falqués-Costa, et al.
BioRxiv, April 26, 2023
PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer.
Brunner A, Suryo Rahmanto A, Johansson H, Franco M, Viiliäinen J, Gazi M, et al
Elife 2020 07;9():
FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.
Suryo Rahmanto A, Savov V, Brunner A, Bolin S, Weishaupt H, Malyukova A, et al
EMBO J. 2016 10;35(20):2192-2212
CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer.
Cepeda D, Ng HF, Sharifi HR, Mahmoudi S, Cerrato VS, Fredlund E, et al
EMBO Mol Med 2013 Jul;5(7):1067-86
Proteomic screen reveals Fbw7 as a modulator of the NF-κB pathway.
Arabi A, Ullah K, Branca RM, Johansson J, Bandarra D, Haneklaus M, et al
Nat Commun 2012 ;3():976
The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling.
Malyukova A, Dohda T, von der Lehr N, Akhoondi S, Akhondi S, Corcoran M, et al
Cancer Res. 2007 Jun;67(12):5611-6
Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line.
Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI
Nature 2001 Sep;413(6853):316-22
Additional recent publications:
A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma.
Cheung BB, Kleynhans A, Mittra R, Kim PY, Holien JK, Nagy Z, Ciampa OC, Seneviratne JA, Mayoh C, Raipuria M, Gadde S, Massudi H, Wong IPL, Tan O, Gong A, Suryano A, Diakiw SM, Liu B, Arndt GM, Liu T, Kumar N, Sangfelt O, Zhu S, Norris MD, Haber M, Carter DR, Parker MW, Marshall GM
Oncogene 2021 Mar;():
FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells.
Shen JZ, Qiu Z, Wu Q, Finlay D, Garcia G, Sun D, et al
Cell 2020 Dec;():
K63-linked ubiquitylation induces global sequestration of mitochondria.
Richard TJC, Herzog LK, Vornberger J, Rahmanto AS, Sangfelt O, Salomons FA, et al
Sci Rep 2020 Dec;10(1):22334
Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities.
Mehtonen J, Teppo S, Lahnalampi M, Kokko A, Kaukonen R, Oksa L, et al
Genome Med 2020 Nov;12(1):99
Ex vivo assessment of targeted therapies in a rare metastatic epithelial-myoepithelial carcinoma.
Mäkelä R, Arjonen A, Suryo Rahmanto A, Härmä V, Lehtiö J, Kuopio T, et al
Neoplasia 2020 09;22(9):390-398