Paakinaho lab: Transcription factor crosstalk in cancers
Our research group investigates transcription factor crosstalk in cancers. Especially we focus on deciphering the action of steroid receptors and pioneer factors in prostate cancer.
Academy of Finland
Sigrid Juséliuksen Säätiö (Sigrid Jusélius Foundation)
Syöpäsäätiö (Cancer Foundation Finland)
Research group description
Detailed description of our research
Transcriptional regulation is one of the most important biological processes in organisms contributing to every aspect of health and disease. Abnormal regulation of transcription can lead to several different disease states, with the most drastic alterations occurring in cancers. Regulation of gene expression through enhancers and promoters is mediated by transcription factors (TFs). At these sites, TFs influence transcriptional regulation by altering the chromatin accessibility and RNA polymerase action via changing the activity and recruitment of other TFs and coregulators. In the past, the action of many TFs has only been investigated in isolation of other TFs/signaling pathways. However, TF practically never work in isolation, wherein only one TF is acting while others remain inactive. Recently it has been indicated that the interplay of TFs can drastically change when multiple pathways are activated in sequence or simultaneously. There are multiple mechanisms how TFs can modulate chromatin binding and the activity of other TFs, such as cooperative binding, tethering, and assisted loading. Interestingly, this TF crosstalk can influence both the progression and drug resistance of cancers as well as the regulation of normal metabolic processes.
Steroid receptors, such as estrogen (ER), androgen (AR), and glucocorticoid receptor (GR), are hormone-controlled TFs that regulate transcription in multiple central cellular systems. The action of steroid receptors have a major role in the development and progression diseases, especially hormone-dependent cancers. The AR influences the progression of prostate cancer (PCa), while the ER (ESR1) is a critical factor for breast cancer (BCa) development. Thus, both receptors are the major drug targets in these cancers; the ER and the AR are targeted by antagonist compounds, or the synthesis of their activating hormones is inhibited. E.g., in PCa, the AR action can be inhibited by enzalutamide (ENZ), a second-generation antiandrogen that competes with androgens for binding to the receptor’s ligand-binding domain. However, despite the effectiveness of these therapies, the cancers frequently bypass the blockade of ER and AR activity through development of drug resistance.
In contrast to ER and AR, GR has long been thought to have a tumor suppressor role, since the receptor can suppress the growth of cancer cells, as exemplified by the effect of glucocorticoids on lymphoblastic leukemia. Furthermore, glucocorticoids are widely used to alleviate therapy-related side-effects and to reduce inflammation in BCa and PCa patients. Despite the beneficial effects of glucocorticoids, recent evidence suggests that GR plays a detrimental role in both BCa and PCa. In BCa, the activation of GR enhances the metastasizing capability of the disease. In PCa, GR is postulated to be an essential player in therapy naïve and antiandrogen-treated cancer.
Coregulators recruited by the ER and AR have been considered as potential targets for cancer therapies. The druggable coregulators include EP300 and various proteins of the bromodomain and extra-terminal (BET) family. Inhibition of the activity of these coregulators have been shown to restrict the action of AR in PCa. In addition to coregulators, pioneer factors, a class of TFs, can have a major impact on the activity of AR and ER in in PCa and BCa, respectively. Especially, the forkhead box A1 (FOXA1), which is frequently mutated and dysregulated in these cancers, is important regulator of steroid receptor chromatin binding. Interestingly, this regulatory capability occurs in symmetric fashion wherein steroid receptors can also modulate the chromatin occupancy of FOXA1. Finally, also other steroid receptors, have emerged as important “coregulators” for the ER and AR in cancer cells. In PCa, the inhibition of AR by ENZ increases the expression of GR, which can lead to GR replacing AR as the driver of PCa progression. Thus, the TF crosstalk can have a major impact on the development and progression of not only therapy naïve but also antiandrogen-resistant PCa.
For more information, see our two review articles on these aspects:
Our research aims to decipher several aspects in TF crosstalk:
(i) What kind of crosstalk mechanism occur between steroid receptors and pioneer factors in benign versus malignant PCa cells.
(ii) How and through what mechanism does GR replace AR signaling in antiandrogen-resistant PCa cells.
(iii) To what degree does coregulators influence TF crosstalk in therapy naïve and antiandrogen-resistant PCa cells.
We expect to discover new therapeutic avenues to target concerted TF action in PCa. The concomitant targeting of steroid receptor with a coregulator could help to resolve drug resistance occurring with single drug treatments. In addition, targeting of GR in antiandrogen-resistant PCa through other signaling pathways could help retain the beneficial systemic effect of glucocorticoids.
Group members - UEF
Ville Paakinaho Academy Research Fellow , School of Medicine, Biomedicine
Laura Helminen School of Medicine, Biomedicine
Other group members
Jasmin Huttunen firstname.lastname@example.org
COLLABORATION - UEF
Publications by the research group members
An intrinsically disordered region-mediated confinement state contributes to the dynamics and function of transcription factors Garcia, David A; Johnson, Thomas A; Presman, Diego M; Fettweis, Gregory; Wagh, Kaustubh; Rinaldi, Lorenzo; Stavreva, Diana A; Paakinaho, Ville; Jensen, Rikke AM; Mandrup, Susanne; Upadhyaya, Arpita; Hager, Gordon L. 2021. An intrinsically disordered region-mediated confinement state contributes to the dynamics and function of transcription factors Molecular cell 81 7: 1484-1498. 2021
Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells Launonen, Kaisa-Mari; Paakinaho, Ville; Sigismondo, Gianluca; Malinen, Marjo; Sironen, Reijo; Hartikainen, Jaana M; Laakso, Hanna; Visakorpi, Tapio; Krijgsveld, Jeroen; Niskanen, Einari A; Palvimo, Jorma J. 2021. Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells Oncogene 40 27: 4567-4579. 2021
Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis Vandewalle, Jolien; Timmermans, Steven; Paakinaho, Ville; Vancraeynest, Lies; Dewyse, Liza; Vanderhaeghen, Tineke; Wallaeys, Charlotte; Van Wyngene, Lise; Van Looveren, Kelly; Nuyttens, Louise; Eggermont, Melanie; Dewaele, Sylviane; Velho, Tiago R; Moita, Luis F; Weis, Sebastian; Sponholz, Christoph; van Grunsven, Leo A; Dewerchin, Mieke; Carmeliet, Peter; De Bosscher, Karolien; et al.; [incl. Pal. 2021. Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis Cell metabolism [In Press, Corrected Proof 23.7. ]: 1-20. 2021
Genome-wide binding potential and regulatory activity of the glucocorticoid receptor's monomeric and dimeric forms Johnson, Thomas A; Paakinaho, Ville; Kim, Sohyoung; Hager, Gordon L; Presman, Diego M. 2021. Genome-wide binding potential and regulatory activity of the glucocorticoid receptor's monomeric and dimeric forms Nature communications 12: 1987. 2021
Genome-wide crosstalk between steroid receptors in breast and prostate cancers Paakinaho, Ville; Palvimo, Jorma J. 2021. Genome-wide crosstalk between steroid receptors in breast and prostate cancers Endocrine-related cancer 28 9: R231-R250. 2021
SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites Paakinaho, Ville; Lempiäinen, Joanna K; Sigismondo, Gianluca; Niskanen, Einari A; Malinen, Marjo; Jääskeläinen, Tiina; Varjosalo, Markku; Krijgsveld, Jeroen; Palvimo, Jorma J. 2021. SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites Nucleic acids research 49 4: 1951-1971. 2021
Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome Paakinaho, V; Johnson, TA; Presman, DM; Hager, GL. 2019. Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome Genome research 29 8: 1223-1234. 2019
Meta-analysis of Chromatin Programming by Steroid Receptors Paakinaho, Ville; Swinstead, Erin E; Presman, Diego M; Grøntved, Lars; Hager, Gordon L. 2019. Meta-analysis of Chromatin Programming by Steroid Receptors Cell reports 28 13: 3523-3534. 2019
Chromatin reprogramming in breast cancer Swinstead, Erin E; Paakinaho, Ville; Hager, Gordon L. 2018. Chromatin reprogramming in breast cancer. ENDOCRINE-RELATED CANCER 25 7: R385-R404. 2018