H2020Индивидуална стипендия2020–2022

RegARcis · Role of the SWI/SNF complex in the Androgen Receptor cistrome regulation

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-03-31 → 2022-03-30
Финансиране от ЕС: 160 932 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Ролята на протеина Nsd2 и комплекса SWI/SNF при рака на простатата се анализира чрез влиянието им върху устойчивостта към антиандрогенна терапия. Разбирането на тези механизми помага за търсенето на нови начини за справяне с терапевтичната резистентност при пациентите.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Role of the SWI/SNF complex in the Androgen Receptor cistrome regulation

Lineage plasticity and trans-differentiation towards cancer cellular state that no longer depends on the drug target and becomes insensitive to the targeted therapy is increasingly renowned as a mechanism of therapeutic resistance. While this has been observed in prostate cancer patients with castration resistant prostate cancer (CRPC) tumors that progress upon anti-androgen receptor (anti-AR) therapies, the molecular boosters remain elusive, thus hampering the development of novel therapeutic strategies. The significance of epigenetic deregulation is a very hot topic in current prostate cancer (PCa) research. New mutations have been identified in several epigenetic regulators known for their interaction with the androgen receptor (AR). Therefore, this MSCA project aimed at elucidating the role of epigenetic regulators such as Nsd2 and the SWI/SNF chromatin-remodeling complex in the emergence of resistance to anti-AR signaling inhibitors in the malignant phenotype of PCa. To achieve this goal during this MSCA, Dr. Rana EL BIZRI (MSCA-IF recipient) and her mentor Dr. Alvaro Aytes (i) explored the potential benefits of targeting Nsd2 and/or the core components of the SWI/SNF complex (Baf155 and Baf170) in CRPC specifically in NPp53 cells; (ii) investigated the changes in the chromatin accessibility mediated by Nsd2 loss and upon anti-AR treatment (e.g. Abiraterone); and (iii) defined the Nsd2-dependent AR interactome. Dr. Rana EL BIZRI (MSCA-IF recipient) and her mentor Dr. Alvaro Aytes concluded during this action that (i) Nsd2 overexpression co-operates with AR to drive metastatic CRPC and resistance to anti-AR therapies; (ii) Nsd2 antagonizes with the SWI/SNF complex and confers resistance to AR signaling inhibitors; (iii) Nsd2 is a potential therapeutic target to re-sensitize metastatic CRPC to anti-AR therapies; (iv) and that targeting the core component of SWI/SNF subunits in the presence of Nsd2 is not efficient to re-sensitize metastatic CRPC to anti-AR therapies. Together, our data suggests that Nsd2 overexpression drives aggressive castration resistant and androgen independent PCa in part through destabilizing SWI/SNF interaction and altering the specificity of the AR cistrome.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The significance of epigenetic deregulation is a very hot topic in current prostate cancer (PC) research. New mutations have been identified in several epigenetic regulators known for their interaction with the AR. In fact, the role of chromatin remodeling factors facilitating enhancer-promoter cooperation in the formation of the AR transcriptional complex has long been demonstrated. Accordingly, the marked redistribution of AR binding sites (cistrome) during tumorigenesis is arguably the most recurrent genetic or epigenetic alterations in PC. Thus, this MCSA project aims at elucidating the role of the SWI/SNF chromatin-remodeling complex in the emergence of resistance to anti-AR signaling inhibitors. This is of utmost importance as resistance to AR signaling inhibition is arguably the principle hallmark of lethal prostate cancer. To this end, I aim at (i) investigating the SWI/SNF dependent chromatin accessibility and AR cistrome; and at (ii) assessing the actionability of SWI/SNF interacting partners in castration resistance prostate cancer (CRPC). In short, this MSCA proposal will help to define the repertoire of SWI/SNF coregulators in CRPC and to determine the extent of AR cistrome remodeling to envision new therapeutic strategies and help predict treatment response.

Оригинален текст от CORDIS (на английски).

Участници

FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE · L'Hospitalet De LlobregatКоординаторИспания