Low expression of FOXP2 predicts poor survival and targets caspase-1 to inhibit cell pyroptosis in colorectal cancer

Abstract

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Several studies have suggested that FOXP2 functions as a tumour suppressor. However, to date, it remains unclear how FOXP2 influences CRC occurrence. Methods: We took advantage of CRC tissue samples and compared the expression of FOXP2 via immunohistochemistry assays. We elucidated the underlying function of FOXP2 in CRC cells by constructing a cell model with FOXP2 depletion. Co-IP experiments and immunofluorescence (IF) assays were conducted, and the results demonstrated that FOXP2 can promote the activation of caspase-1 to enhance cell pyroptosis. Results: We used tissue RNA sequencing analysis in a colitis-associated cancer mouse model, and found that FOXP2 was downregulated in colitis and tumour tissues. We also found that CRC patients with low FOXP2 expression had poorer survival. Cell viability assays and electron microscopic examination showed that depletion of FOXP2 could enhance cell growth and inhibit cell pyroptosis. At the same time, knocking down FOXP2 expression was able to promote the protein expression of PCNA and cyclin D1 and downregulate the expression of the caspase family of proteins and GSDMD, which are markers of pyroptosis. A series of co-IP and IF assays revealed that FOXP2 interacts with caspase-1 and promotes its expression. Conclusion: Our findings reveal a key role for FOXP2 in CRC cell pyroptosis and provide a mechanism explaining how FOXP2 promotes cell pyroptosis.

FOXP2 inhibits the aggressiveness of lung cancer cells by blocking TGFβ signaling

“…For instance, FOXP2 epigenetically activates RPS6KA6 to enhance tumor cell apoptosis in thyroid cancer (31). FOXP2 interacts with caspase-1 to drive tumor cell pyroptosis in colorectal cancer (23). In the present study, FOXP2 blocked TGFβ signaling, which plays a key role in the pathogenesis of cancers.…”

“…TGFβ/SMAD is involved in the carcinogenesis of lung cancer (23)(24)(25). FOXP2 overexpression suppresses tumor aggressiveness.…”

Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance

“…Mechanistic studies have shown that FOXP2 interacts with caspase‐1 and promotes its expression. [ 198 ] Metformin can inhibit tumor progression by inducing pyroptosis in ESCC by targeting the miR‐497/Proline‐, glutamic acid‐ and leucine‐rich protein 1 (PELP1) axis. [ 199 ] Photodynamic therapy can treat ESCC by inducing GSDME‐mediated pyroptosis, and PDT can activate caspase‐8 and caspase‐3 via Pyruvate kinase Pyruvate kinase (PKM2) to ultimately release GSDME‐N and trigger pyroptosis in ESCC cells.…”

RSAD2, a pyroptosis-related gene, predicts the prognosis and immunotherapy response for colorectal cancer

“…Pyroptosis, a new form of programmed cell death, leads to cleavage of gasdermin D (GSDMD) and activates inflammatory factors [4,5]. Substantial evidence suggests that pyroptosis plays a critical role in immune response and tumor progression, including CRC [6][7][8]. Long-term chronic pyroptosis of cancer cells triggered by the tumor microenvironment (TME) is more likely to promote cancer progression [9].…”