Upregulation of mtSSB by interleukin‐6 promotes cell growth through mitochondrial biogenesis‐mediated telomerase activation in colorectal cancer

Abstract

It is now widely accepted that mitochondrial biogenesis is inhibited in most cancer cells. Interestingly, one of the possible exceptions is colorectal cancer (CRC), in which the content of mitochondria has been found to be higher than in normal colon mucosa. However, to date, the causes and effects of this phenomenon are still unclear. In the present study, we systematically investigated the functional role of mitochondrial single‐strand DNA binding protein (mtSSB), a key molecule in the regulation of mitochondrial DNA (mtDNA) replication, in the mitochondrial biogenesis and CRC cell growth. Our results demonstrated that mtSSB was frequently upregulated in CRC tissues and that upregulated mtSSB was associated with poor prognosis in CRC patients. Furthermore, overexpression of mtSSB promoted CRC cell growth in vitro by regulating cell proliferation. The in vivo assay confirmed these results, indicating that the forced expression of mtSSB significantly increases the growth capacity of xenograft tumors. Mechanistically, the survival advantage conferred by mtSSB was primarily caused by increased mitochondrial biogenesis and subsequent ROS production, which induced telomerase reverse transcriptase (TERT) expression and telomere elongation via Akt/mTOR pathway in CRC cells. In addition, FOXP1, a member of the forkhead box family, was identified as a new transcription factor for mtSSB. Moreover, our results also demonstrate that proinflammatory IL‐6/STAT3 signaling facilitates mtSSB expression and CRC cell proliferation via inducing FOXP1 expression. Collectively, our findings demonstrate that mtSSB induced by inflammation plays a critical role in the regulation of mitochondrial biogenesis, telomerase activation, and subsequent CRC proliferation, providing a strong evidence for mtSSB as drug target in CRC treatment.

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

“…We found that this is due to a compensatory response initiated by a transcriptional activation of the mitochondrial stress response master regulator CEBPβ, which acts to increase mitochondrial biogenesis in concert with ATF4 and CHOP via TFAM but also by increasing cellular proliferation in the liver via increased telomerase expression (Fig ). This is a previously unreported transcriptional response that appears to be distinct from the post‐transcriptional signaling pathways that increase mitochondrial biogenesis in response to energy demands (Morita et al , ) or that upregulate telomerase in response to increased mitochondrial biogenesis (Wang et al , ), as both of these act via the mTOR pathway, that is not activated by the low levels of stress that result from mitochondrial mistranslation in our model. Post‐transcriptional responses are more rapid than transcriptional responses and are better suited to deal with extreme stresses, while the transcriptional responses we observe are potentially better suited to improve the stability of mitochondrial function over a longer timeline.…”

<p>Progress in Understanding the IL-6/STAT3 Pathway in Colorectal Cancer</p>

“…The expressed mtSSB activates the ROS/Akt/mTOR pathway, which up-regulates telomerase reverse transcriptase (TERT), which stabilizes telomeres and thereby helps immortalize CRC cells. 54…”

CASC21, a FOXP1 induced long non-coding RNA, promotes colorectal cancer growth by regulating CDK6

“…Remarkably, FOXP1 is identified to act as an oncogene, and its overexpression confers a poor prognosis in various types of cancers [43][44][45][46]. A recent study has demonstrated that FOXP1 participated in promoting the proliferation of CRC cells, and its high expression suggests poor prognosis of CRC patients [47].…”