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Reciprocal regulation of Daxx and PIK3CA promotes colorectal cancer cell growth

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Upregulation of death-domain-associated protein (Daxx) is strongly associated with diverse cancer types. Among these, the clinicopathological significance and molecular mechanisms of Daxx overexpression in colorectal cancer (CRC) remain unknown. Here, we showed that Daxx expression was increased in both clinical CRC samples and CRC cell lines. Daxx knockdown significantly reduced proliferation activity in CRC cells and tumor growth in a xenograft model. Further studies revealed that Daxx expression could be attenuated by either treatment with the PIK3CA inhibitor PIK-75 or PIK3CA depletion in CRC cells. Conversely, expression of PIK3CA constitutively active mutants could increase Daxx expression. These data suggest that PIK3CA positively regulates Daxx expression. Consistently, the expression levels of PIK3CA and Daxx were positively correlated in sporadic CRC samples. Interestingly, Daxx knockdown or overexpression yielded decreased or increased levels of PIK3CA, respectively, in CRC cells. We further demonstrated that Daxx activates the promoter activity and expression of PIK3CA. Altogether, our results identify a mechanistic pathway of Daxx overexpression in CRC and suggest a reciprocal regulation between Daxx and PIK3CA for CRC cell growth.

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We thank Dr. Chi-Jung Huang and Mrs. Hsiao-Ting Tseng for CCD18-co cells, Dr. Noriyuki Tsumaki for PIK3CA reporter construct, Dr. Scott Lowe for MSCV Luciferase PGK-hygro plasmid, Dr. Feng Zhang for pX330 construct and Dr. Bert Vogelstein for PIK3CA H1047R and E545K plasmids, respectively. We are grateful to Dr. Shun-Yuan Jiang, Dr. Po-Hsun Tu, Dr. Wei-Chih Yang, and Mr. Pei-Hsiang Hou for their excellent technical support.


This work was supported by grants from the Ministry of Science and Technology (MOST 110-2327-B-001-001 and 108-2320-B-001-035-MY3), Taiwan.

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Conceptualization: YSH, CCW, and HMS; performing experiments: YSH, CCC, and HYK; data analysis: CCW and SFH; drafting and editing YSH and HMS.

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Correspondence to Yen-Sung Huang or Hsiu-Ming Shih.

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The questionnaire and methodology for this study were approved by the Human Research Ethics committee of the Tri-Service General Hospital (Ethics approval number: 098-05-292). All animal handling was approved by the Ethical Committee on Animal Experiments, Academia Sinica, Taiwan (IACUC-approved ptotocol#2009-018).

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Huang, YS., Wu, CC., Chang, CC. et al. Reciprocal regulation of Daxx and PIK3CA promotes colorectal cancer cell growth. Cell. Mol. Life Sci. 79, 367 (2022).

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