With sequence similarities to exogenous retroviruses, the proviral DNA elements named endogenous retroviruses (ERVs) make up ∼8% of human genome, threatening genomic stability meanwhile nurturing regulatory innovations. Diverse host epigenetic mechanisms are enlisted to limit the ERVs’ activity. However, in certain physiological and pathophysiological processes, distinct ERVs become abnormally activated, rewiring and perplexing the host regulons at different levels (Cosby et al., 2019). ERVs not only contribute to the nuclear architecture; once activated, they can also act as enhancers, promoters, or even be exonized to shape the transcriptional circuitries. Moreover, some ERVs are able to synthesize regulatory noncoding RNA species or functional polypeptides to impact the transcriptome as well as the proteome. As one of the most abundant ERV groups, the transcriptional activation of human endogenous retrovirus H (HERVH) is crucial for the acquisition and maintenance of the pluripotent state of human embryonic stem cells (ESCs) as well as the induced pluripotent stem cells (Rodriguez-Terrones and Torres-Padilla, 2018). HERVH is also active in several types of cancer including colorectal cancer (CRC), yet how it is activated and influences carcinogenic signaling pathways remains largely unclear.