MiniSOX9, a dominant-negative variant in colon cancer cells

Abdel-Samad, Rana; Zalzali, Hassan; Rammah, C.; Giraud, Julie; Naudin, Cécile; Dupasquier, Sébastien; Poulat, Françis; Boizet-Bonhoure, Brigitte; Lumbroso, Serge; Mouzat, Kévin; Bonnans, Caroline; Pignodel, C; Raynaud, Peggy; Fort, Philippe; Quittau-Prévostel, Corinne; Blache, Philippe

doi:10.1038/onc.2010.621

Cited by 34 publications

(37 citation statements)

References 40 publications

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“…We previously described a mutation that affects the splicing donor site of intron2 of SOX9 in the DLD-1 cell line [9]. In the present study, we report an additional inactivating mutation on the same allele while the second allele of SOX9 remains unaffected.…”

Section: Resultssupporting

confidence: 66%

“…It is responsible for a weak transcriptional activity of SOX9 as evidenced by the weak SOX-dependent luciferase activity of the transiently expressed L142P mutant compared with the wild type SOX9 (Figure 1B). Thus, it is likely that the L142P inactivating mutation of SOX9 and the expression of MiniSOX9 [9] both contribute not only to a weak SOX9 transcriptional activity in DLD-1 cells (Figure 1B, empty vector lane), but also to a loss of the SOX9 dependent inhibition of the activity of the oncogenic Wnt/ß-catenin signaling pathway. Indeed, when expressed at a level similar to a wild type SOX9 (Figure 1D), the L142P mutant is unable to decrease the Top Flash dependent luciferase activity (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, it has to be taken into account that SOX9 transcriptional activity is low in intestinal tumor cell lines [7] and this might be due, at least partly, to inactivating mutations of the SOX9 gene [8], but also to our discovery of MiniSOX9 in colon cancer cells. MiniSOX9 is indeed a SOX9 splice variant that behaves as a dominant negative with respect to SOX9 while competing with SOX9 for DNA binding [9]. Thus, both SOX9 mutations and MiniSOX9 expression are likely to contribute to SOX9 inactivation in CRC.…”

Section: Introductionmentioning

confidence: 99%

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SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling

et al. 2016

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SOX9 inactivation is frequent in colorectal cancer (CRC) due to SOX9 gene mutations and/or to ectopic expression of MiniSOX9, a dominant negative inhibitor of SOX9. In the present study, we report a heterozygous L142P inactivating mutation of SOX9 in the DLD-1 CRC cell line and we demonstrate that the conditional expression of a wild type SOX9 in this cell line inhibits cell growth, clonal capacity and colonosphere formation while decreasing both the activity of the oncogenic Wnt/ß-catenin signaling pathway and the expression of the c-myc oncogene. This activity does not require SOX9 transcriptional function but, rather, involves an interaction of SOX9 with nuclear ß-catenin. Furthermore, we report that SOX9 inhibits tumor development when conditionally expressed in CRC cells injected either subcutaneous or intraperitoneous in BALB/c mice as an abdominal metastasis model. These observations argue in favor of a tumor suppressor activity for SOX9. As an siRNA targeting SOX9 paradoxically also inhibits DLD-1 and HCT116 CRC cell growth, we conclude that there is a critical level of endogenous active SOX9 needed to maintain CRC cell growth.

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling

et al. 2016

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“…Interestingly, studies have shown overexpression of an isoform of the SOX9 protein in CRC that is truncated due to retention of intron 2 (termed ‘miniSOX9’), missing the transactivation domain yet still conserving the N terminal dimerization and DNA binding domains [15]. …”

Section: Discussionmentioning

confidence: 99%

Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

et al. 2016

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PurposeThe extent to which the developmental transcription factor SOX9 functions as an oncogene or tumor suppressor in colorectal carcinoma (CRC) is debatable. We aimed to clarify the effect of SOX9 mutations on SOX9 protein expression and their association with known molecular subtypes and clinical characteristics in advanced CRC.Experimental DesignNext generation sequencing data (MSK-IMPACT) from CRC patients was used to interrogate SOX9, KRAS, NRAS, BRAF, TP53, APC, and PIK3CA. Mutant and wild type (WT) SOX9 cases underwent immunohistochemical (IHC) staining to assess protein expression. SOX9 allele-specific copy number was assessed by Affymetrix Oncoscan array.ResultsSOX9 was mutated in 38 of 353 (10.7%) CRC, of which 82% were frameshift or nonsense. Compared to SOX9 WT, SOX9 mutation was strongly associated with coexistent mutant KRAS (p=0.0001) and WT TP53 (p=0.0004). SOX9 was overexpressed in both SOX9 mutant and WT CRC. Among SOX9 mutants, the highest expression was noted for truncating exon 3 mutants (mean H scores 239±105 versus 147±119, p value=0.02). Further, SOX9 truncating mutants with loss of the WT allele demonstrated protein overexpression indicating the WT protein was not required for protein stabilization.ConclusionsSOX9 is overexpressed in CRC, including those with recurrent distal truncating mutations. The latter has structural similarity to the oncogenic isoform MiniSOX9, which is distally truncated due to aberrant splicing. This information suggests that truncated SOX9 has oncogenic features. SOX9 mutations are highly enriched in KRAS mutant and TP53 wild type CRC; and may provide a therapeutic target in approximately 11% of CRC.

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“…Clinico-pathologically, high SOX9 expression correlates with tumor progression and advanced tumor stage18 and has been associated with lower overall patient survival2021. Functional studies have supported the view that SOX9 plays a pro-oncogenic role in primary colorectal cancer cells1821, but under some circumstances it behaves as a tumor suppressor2526. The role of SOX9 in the regulation of CR-CSCs has not been previously explored.…”

mentioning

confidence: 99%

SOX9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin

Carrasco‐García

López

Aldaz

et al. 2016

Sci Rep

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The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9-dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.

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MiniSOX9, a dominant-negative variant in colon cancer cells

Cited by 34 publications

References 40 publications

SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling

SOX9 is an atypical intestinal tumor suppressor controlling the oncogenic Wnt/ß-catenin signaling

Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

SOX9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin

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