The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer

Abstract

Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells.

Can uric acid affect the immune microenvironment in bladder cancer? A single‐center multi‐omics study

“…Moreover, as an oncogene, the overexpression of TFCP2L1 can promote the proliferation, invasion, and stemness features of BCa 51 . CDK1 phosphorylates Tfcp2l1 at Thr177, which modulates the stemness features and survival of BCa cells through the involvement of the inhibitor of DNA binding‐2 52 . Additionally, the expression of IGF2 is commonly elevated in BCa and is correlated with inferior OS and progression‐free survival 53 .…”

“…51 CDK1 phosphorylates Tfcp2l1 at Thr177, which modulates the stemness features and survival of BCa cells through the involvement of the inhibitor of DNA binding-2. 52 Additionally, the expression of IGF2 is commonly elevated in BCa and is correlated with inferior OS and progression-free survival. 53 Many studies have highlighted the potential utility of IGF2 as a urinary biomarker in the noninvasive detection of potential patients with BCa.…”

Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

“…Increased expression of Tfcp2l1 in lung and bladder cancer has been linked to poor prognosis and aggressive phenotypes, whereas decreased expression has been linked to a decrease in cancer progression (Heo et al, 2020; Kotarba et al, 2018). Cdk1 phosphorylation of Tfcp2l1 also appears to regulate its ability to promote proliferation in bladder cancer (Heo et al, 2022; Heo et al, 2020). Together, these findings reveal an integral role for Tfcp2l1 in transmitting Wnt signals to promote cell cycle progression in multiple stem cell lineages, including AT2 cells.…”

PIN1 and CDK1 cooperatively govern pVHL stability and suppressive functions

“…When tumors reached 400 mm 3 in size, the primary tumors were removed. Animals were randomly allocated to different groups and administrated by Vehicle, ATRA (1.5 mg/kg) [ 21 ] or RO-3306 (4 mg/kg) [ 22 ] every two days until sacrifice. Cisplatin (2 mg/kg) were administrated for three times weekly after xenografting.…”