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PUMILIO proteins promote colorectal cancer growth via suppressing p21.

ABSTRACT: PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under-explored. Here, we report that Pum1 and Pum2 display increased expression in human colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 in mice significantly inhibits the progression of colitis-associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 in human CRC cells result in a significant decrease in the tumorigenicity and delayed G1/S transition. We identify p21/Cdkn1a as a direct target of PUM1. Abrogation of the PUM1 binding site in the p21 mRNA also results in decreased cancer cell growth and delayed G1/S transition. Furthermore, intravenous injection of nanoparticle-encapsulated anti-Pum1 and Pum2 siRNAs reduces colorectal tumor growth in murine orthotopic colon cancer models. These findings reveal the requirement of PUM proteins for CRC progression and their potential as therapeutic targets.

SUBMITTER: Gong Y

PROVIDER: S-EPMC8956581 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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PUMILIO proteins promote colorectal cancer growth via suppressing p21.

Gong Yuanyuan Y Gong Yuanyuan Y Liu Zukai Z Yuan Yihang Y Yang Zhenzhen Z Zhang Jiawei J Lu Qin Q Wang Wei W Fang Chao C Lin Haifan H Liu Sanhong S

Nature communications 20220325 1

PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under-explored. Here, we report that Pum1 and Pum2 display increased expression in human colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 in mice significantly inhibits the progression of colitis-associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 in human CRC ...[more]

PMID: 35338151

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Project description:BackgroundCancer stem cells (CSCs) have been recognized as an important drug target, however, the underlying mechanisms have not been fully understood. SKP1 is a traditional drug target for cancer therapy, while, whether SKP1 promotes colorectal cancer (CRC) stem cells (CRC-SCs) and the underlying mechanisms have remained elusive.MethodsHuman CRC cell lines and primary human CRC cells were used in this study. Gene manipulation was performed by lentivirus system. The mRNA and protein levels of target genes were examined by qRT-PCR and western blot. The sphere-forming and in vitro migration capacities were determined by sphere formation and transwell assay. The self-renewal was determined by limiting dilution assay. The tumorigenicity and metastasis of cancer cells were examined by xenograft model. The promoter activity was examined by luciferase reporter assay. Nuclear run-on and Chromatin immunoprecipitation-PCR (ChIP-PCR) assay were employed to examine the transcription and protein-DNA interaction. Co-immunoprecipitation assay was used to test protein-protein interaction. The relationship between gene expression and survival was analyzed by Kaplan-meier analysis. The correlation between two genes was analyzed by Spearman analysis. Data are represented as mean ± SD and the significance was determined by Student's t test.ResultsSKP1 was upregulated in CRC-SCs and predicted poor prognosis of colon cancer patients. Overexpression of SKP1 promoted the stemness of CRC cells reflected by increased sphere-forming, migration and self-renewal capacities as well as the expression of CSCs markers. In contrast, SKP1 depletion produced the opposite effects. SKP1 strengthened YAP activity and knockdown of YAP abolished the effect of SKP1 on the stemness of CRC cells. SKP1 suppressed RASSF1 at both mRNA and protein level. Overexpression of RASSF1 abolished the effect of SKP1 on YAP activity and CRC stemness.ConclusionOur results demonstrated that SKP1 suppresses RASSF1 at both mRNA and protein level, attenuates Hippo signaling, activates YAP, and thereby promoting the stemness of CRC cells.

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PUMILIO proteins promote colorectal cancer growth via suppressing p21.

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PUMILIO proteins promote colorectal cancer growth via suppressing p21.

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