HES1 promoter activation dynamics reveal the plasticity, stemness and heterogeneity in neuroblastoma cancer stem cells

Journal of Cell Science  | November 18, 2022 | https://doi.org/10.1242/jcs.260157

Paul Ann Riya, Budhaditya Basu, Suresh Surya, Surendran Parvathy, Soundararajan Lalitha , Nair Pradeep Jyothi, Vadakkath Meera, Vishnu Sunil Jaikumar, Padmanabhan Sunitha, Afzal Shahina, Rashmi Sukumaran, Achuthsankar Sukumaran Nair, Sivadasan Bindu Dhanesh, John Jiffy, Shijulal Nelson-Sati , Tessy Thomas Maliekal, Ani Venmanad Das, Jackson James

ABSTRACT

Notch signaling and its downstream gene target HES1 play a critical role in regulating and maintaining cancer stem cells (CSCs), similar to as they do during embryonic development. Here, we report a unique subclass of Notch-independent Hes-1 (NIHes-1)-expressing CSCs in neuroblastoma. These CSCs maintain sustained HES1 expression by activation of HES1 promoter region upstream of classical CBF-1 binding sites, thereby completely bypassing Notch receptor-mediated activation. These stem cells have self-renewal ability and potential to generate tumors. Interestingly, we observed that NIHes-1 CSCs could transition to Notch-dependent Hes-1-expressing (NDHes-1) CSCs where HES1 is expressed by Notch receptor-mediated promoter activation. We observed that NDHes-1-expressing CSCs also had the potential to transition to NIHes-1 CSCs and during this coordinated bidirectional transition, both CSCs gave rise to the majority of the bulk cancer cells, which had an inactive HES1 promoter (PIHes-1). A few of these PIHes-1 cells were capable of reverting into a CSC state. These findings explain the existence of a heterogenic mode of HES1 promoter activation within the IMR-32 neuroblastoma cell line and the potential to switch between them.

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