RB/E2F1 as a Master Regulator of Cancer Cell Metabolism in Advanced Disease

Abstract

Loss of the retinoblastoma (RB) tumor suppressor protein is a critical step in reprogramming biological networks that drive cancer progression, although mechanistic insight has been largely limited to the impact of RB loss on cell cycle regulation. Here, isogenic modeling of RB loss identified disease stage-specific rewiring of E2F1 function, providing the first-in-field mapping of the E2F1 cistrome and transcriptome after RB loss across disease progression. Biochemical and functional assessment using both in vitro and in vivo models identified an unexpected, prominent role for E2F1 in regulation of redox metabolism after RB loss, driving an increase in the synthesis of the antioxidant, glutathione, specific to advanced disease. These E2F1-dependent events resulted in protection from reactive oxygen species (ROS) in response to therapeutic intervention. On balance, these findings reveal novel pathways through which RB loss promotes cancer progression and highlight potentially new nodes of intervention for treating RB-deficient cancers.Research.

The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1

“…The first major finding is that two key transcriptional regulators involved in carcinogenesis, FOXM1 and E2F1, are reduced in cells with TRPM2 deletion compared to control cells 38 , 55 . FOXM1 is expressed in highly proliferative cells including progenitor cells and regenerating tissue, and both FOXM1 and E2F1 are master regulators in cancer 38 – 40 , 56 . FOXM1 has a key role in promoting tumor cell proliferation, cell cycle progression, DNA damage repair, angiogenesis, and drug resistance, and elevated FOXM1 correlates with poor prognosis in many cancers 38 , 39 , 57 .…”

“…E2F transcription factors, CREB, and HIF-1/2α all promote FOXM1 transcription and expression 38 , 39 . E2Fs, particularly E2F1, also function as master regulators in cancer and regulate a number of pathways which promote proliferation 40 .…”

Exploiting the tumor-suppressive activity of the androgen receptor by CDK4/6 inhibition in castration-resistant prostate cancer

“…We first examined the chromatin binding of p130 in C4-2-tet-shRB cells using ChIP-seq analyses. In the untreated cells, the majority of Rb-binding sites ($80%) and E2F1-binding sites 28 ($60%) were overlapped with p130 binding ($25% and $70% of its total binding sites, respectively; Figures 3A and 3B), suggesting that p130 may function alternatively to Rb to form complexes with E2Fs. Examining several previously identified Rb-binding sites, we confirmed the occupancy of p130, which can be similarly enhanced by the androgen treatment (Figure S6B).…”

“…RB1 loss leads to an expansion of E2F1 cistrome, increased redox metabolism, and lineage plasticity, and is associated with the resistance to ARsignaling-inhibition therapies. [24][25][26][27][28] Our previous studies have shown that AR can recruit hypophosphorylated Rb to DNA replication gene loci and strengthens the activity of Rb-E2F suppressor complex. 5 However, it is still unclear how Rb globally mediates this transcriptional repressor activity of AR in CRPC and whether enhancing Rb-E2F transcriptional repression activity can exploit the tumor-suppressive function of high-T in vivo.…”

Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers

“…SCLC is most notably characterized by loss of RB1 and P53, both of which regulate various metabolic pathways (Table 1) (28,(73)(74)(75), therefore the observation of metabolic differences based on these alone would not provide unique and targetable pathways. Metabolically, the most well studied subcategories of SCLC are driven by ASCL1 and MYC expression.…”